�������Introduction to Sterile Pharmaceutical Preparations

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Learning Tasks

• By the end of this session you are expected to be able to:
1. Define sterile pharmaceutical products.
2. Classify categories of sterile pharmaceutical Products.
3. List qualities of sterile pharmaceutical products.
4. Explain the role of aseptic techniques in assuring quality in pharmaceutical production

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Definition of Sterile Pharmaceutical Products

• Sterile pharmaceutical products refer to pharmaceutical products that are free from any viable microorganisms, these are pharmaceutical products from which viable micro-organisms must be totally absent.
• The production of sterile products requires special care and attention in order to eliminate microbial and particulate contamination at all stages of manufacture and wherever possible also includes a terminal sterilization process.

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Point to note.

• Not all pharmaceutical products need to be sterile. Sterility is insisted on the following products:
1. Parenterally administered products e.g. injections, irrigations, ophthalmology products etc.
2. Pharmaceutical products that come into direct contact with broken skin/mucous membrane or internal organs e.g. certain instruments, sutures, surgical dressings etc.
• These products are required to be prepared and maintained in a sterile state until used.

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Qualities of Sterile Pharmaceutical Products

• Note
• All products intended for sterilization should be manufactured under clean conditions and therefore will be of low microbial content (bioburden) prior to sterilization

Sterile formulations must meet the following standard of quality:

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• Should be sterile
• Free from particulate contaminants
• Free from Pyrogens
• Should be physically and chemically stable
• Should have the same pH as the blood; (isohydric means the same concentration of H⁺ (Hydrogen ions) or pH = 7.38

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Qualities of Sterile Pharmaceutical Products cont…

7. Same Osmotic pressure as blood plasma (isotonic)
8. Coloring agents should not be used
9. Must be prepared under aseptic conditions.
10. Packaging must be specific and of high quality

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What is aseptic technique

• This is a method of handling sterile materials by employing techniques, which minimize the chances of microbial contamination in order to obtain the sterile products.

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How to achieve sterility for pharmaceutical product

• Sterility is maintained by using sterile materials and controlled working environment
• All containers and apparatus used should be sterilized
• Personnel should have training in the control of contamination
• By ensuring that sterile products do not contain any viable bacteria, yeasts or fungi, protozoa, viruses, prions, mycoplasmas or rickettsiae

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Take home assignment

• Discuss different methods for sterilization of pharmaceutical products and medical devices

Roles of aseptic techniques in assuring the quality in pharmaceutical production;

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• To minimize and reduce the risks of contamination
• To disinfect working area, equipment and ingredients in order to attain sterility.
• To prevent access of viable micro-organisms and particulate contamination during preparation and testing of pharmaceutical products

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Categories of Sterile Pharmaceutical products & medical devices

1. Injections, examples
• Intravenous infusions
• Intravenous additives
• Total Parenteral nutrition (TPN) fluids
• Small-volume injections
• Small-volume oily injections

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Categories of Sterile products cont…

2. Non-Injectable sterile fluids, examples
1. Non-injectable water, (Sterile water for irrigation)
2. Urological irrigation solutions,
3. Peritoneal dialysis solutions,
4. Haemodialysis solutions,
5. Inhaler solutions

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Categories of Sterile products cont…

3. Ophthalmic preparations examples,
1. Eye drops
2. Eye lotions
3. Eye ointments
4. Contact lens solutions
5. Wetting solutions
6. Cleaning solutions
7. Soaking solutions

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Categories of Sterile �products cont…

4. Intravenous additives
• These are sterile drugs or additives regularly added to infusions immediately before administration. Examples,
1. Potassium chloride
2. Lidocaine (lignocaine)
3. Heparin
4. certain vitamins
5. Antimalarial injection, eg. Quinine injection
6. Antibiotics.

Categories of Sterile products cont…

5. Surgical dressings, examples
1. Paraffin gauze dressing
2. Semi permeable adhesive dressing
3. Absorbent cotton wool
4. Elastic adhesive dressing
5. Plastic wound dressings
6. Absorbent cotton gauze
7. Gauze pads
8. Absorbent viscose wadding

Categories of Sterile products cont…

6. Implants
• Implants are small, sterile cylinders of drug, inserted beneath the skin or into muscle tissue to provide slow absorption and prolonged action therapy. Examples,
1. Small, sterile cylinders of drug, E.g. Hormones.

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Categories of Sterile products cont…

7. Absorbable haemostats
• consist of a soft pad of solid material packed around and over the wound that can be left in situ and absorbed by body tissues over a period of time, usually up to 6 weeks and to act as a matrix for complete blood clotting.
1. Oxidized cellulose
2. Absorbable gelatin sponge
3. Human fibrin foam
4. Calcium alginate.

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Categories of Sterile products cont…

8. Surgical ligatures and sutures
• These are strands of material used to tie off blood or other vessels (ligature) and to stitch wounds (suture) in surgery. examples
• Sterilized surgical catgut
• This consists of absorbable strands of collagen derived from mammalian tissue, particularly the intestines of sheep.
• Non–absorbable Sutures and ligatures; e.g. linen, nylon, silk and polypropylene

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Categories of Sterile products cont…

9. Instruments and equipment - examples
1. Instruments that may be required in a sterile condition includes syringes (glass or plastic disposable), needles,
2. giving sets, metal surgical instruments (e.g. scalpels, scissors, forceps), rubber gloves, catheters, etc
3. Equipment such as pressure transducers, pacemakers, kidney dialysis equipment, incubators, Respirator parts, medical devices and endoscopes

Evaluation.

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1. Define sterile pharmaceutical products
2. What are the roles of aseptic techniques in assuring quality in pharmaceutical production?
3. Classify categories of sterile pharmaceutical Products

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References

• Senya, S. S., Mwasha, C. Y. S., Muyinga, A. M., Amiri, R. I., & Mauga, E. A. S. K. (2011). Tanzania Pharmaceutical Handbook (2nd ed.). Dar es salaam. 
• A. J. Winfield, J. A. R., I. Smith. (2009). Pharmaceutical Practice (4th ed.) British 
• Britain, R. P. S. o. G. (1994). The Pharmaceutical Codex (12 ed.). London: London Pharmaceutical Press.

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SESSION 2�Aseptic Processing

Learning Tasks

• By the end of this session students are expected to be able to:
1. Give introduction of aseptic processing.
2. Explain concept of aseptic processing
3. Identify basic rules for effective aseptic processing

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Aseptic processing:

• Is the processing and packaging of a commercially sterile product into sterilized containers followed by hermetic sealing with a sterilized closure in a manners that prevents viable microbiological recontamination of the sterile product.

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Aseptic processing cont…

• It require careful control of the aseptic environment, of personnel practices and procedures, sterilization of equipment and components, extensive environmental monitoring, and many other controls.
• The number of controls required and the severe consequences of control failure make aseptic processing one of the highest-risk pharmaceutical processes. Quality risk management is an essential tool in ensuring product quality.

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Concept of Aseptic Processing

• What is Asepsis?

• Asepsis: “ A state of control achieved by using an aseptic work area and performing activities in a manner that prevents microbiological contamination of the exposed sterile product”

Concept of Aseptic Processing cont…

• Suitable measures must be taken to ensure the microbiological quality of pharmaceutical preparations during manufacture but also during packaging, storage and distribution

The requirements necessary to achieve strict asepsis include:

• sterile starting materials
• Sterile equipment
• Controlled environment
• Sterile containers
• Suitable technique by trained personnel

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Aseptic techniques

Basic rules for effective aseptic processing

1. Use a ‘no touch’ technique whenever possible.
• Handle small articles with sterile forceps and, when sterile apparatus must be touched, handle as distant as possible from the part which will come into contact with a sterile liquid or solid, this rule applies even though sterile gloves may be worn
2. Reduce air disturbances to a minimum
• Standard procedures should be designed to minimize movement of personnel within the clean room. Objects should be positioned within reach under the laminar air flow cabinet. Sharp and sudden movements should be avoided.

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Aseptic process basic rules cont…

3. Consider the arrangement of objects under the laminar air flow (LAF)
• Clean air should not flow over dirty articles to contaminate sterile articles, the cabinet should not be loaded with unnecessary equipment, and materials required should be carefully selected and arranged before beginning the procedure.
4. Refuse to be distracted
• No interruption should be allowed until a set procedure has been completed.

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LAMINAR AIR FLOW

Evaluation

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1. What is aseptic processing?
2. What is the requirements necessary to achieve strict asepsis

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END

SESSION 3�Requirements for Sterile Production

Learning Tasks

• By the end of this session students are expected to be able to:
1. Explain premise requirements for sterile production.
2. Explain personnel requirements for sterile production.
3. Explain raw materials requirements for sterile production.
4. Explain documentation requirements for sterile production.
5. Explain equipment requirements for sterile production.

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Introduction

• The quality of infusions produced will depends very much on the degree of care taken during its preparation.
• Each step in the production process is a possible source of contamination to the manufactured product.

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Introduction cont…

• Hence, Manufacture of sterile preparations (e.g. infusions) needs special requirements to minimise the risks of particulate, microbial and pyrogens contamination.
• Therefore, production of sterile preparations needs environmental control of particulate and microbial contamination, so as to reduce the introduction, generation, and retention of contaminants during preparation.

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Premise Requirements for Sterile Production

1. Well maintained premises:

1. The facilities for the manufacture of sterile products should be designed for near to perfect level of cleanliness.
2. The maximum degree of cleanliness must be achieved in the aseptic filling rooms.
3. The surrounding areas should provide a buffer area in which standards of cleanliness are only slightly lower than the aseptic rooms.

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1. Well maintained premises cont...

4. The prevention of contamination must be the primary objective in the design of these facilities.
5. Well-maintained premise is a good indicator that production of infusions is done in clean environment that reduces risks of contamination to the product.

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2. Methods of cleansing:

1. All equipment and surrounding work area must be cleaned thoroughly at the end of the working day.
2. After thorough cleaning, all surfaces should be disinfected, at least in the aseptic area.
3. An effective liquid disinfectant should be sprayed or wiped on all surface.
4. Irradiation from UV lamps properly located will further reduce the viable microorganisms on surfaces and in the air. 

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3. Production Flow pattern:

1. The facility should be designed in such a way that it provides a continuous flow of production activities.
2. A change area has to be available before entering the facilities to allow change of street clothes into the appropriate production garments and gear.
3. There should then be a continuous process from supply storage to compounding of product, filling, sealing, sterilisation, labelling/packaging and finally to storage of the finished product.

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Personnel Requirements for Sterile Production

1. Should be adequately trained and motivated e.g. Equipped with basic understanding of pharmaceutical technology, microbiology and hygiene.
2. They should be aware of the role that every movement has, in determining the quality of the final product. e.g. Aware of the sources of contamination.
3. Appropriate protective clothing should be worn. e.g. Boots, coats, caps, gloves, hats, and mask.

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Personnel Requirements for Sterile Production cont…

4. Only a minimum number of personnel should work in clean areas
5. Personnel working in clean areas should maintain high standards of hygiene and cleanliness.
6. They should undergo periodic health checks, wear clothing that do not shed particles, and should take care not to introduce microbiological contaminants in the areas.

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Personnel requirement in sterile production

Personnel working in aseptic areas should be required to follow laid down preparatory procedures

1. Removing outside street clothing, scrubbing the hands and arms thoroughly with disinfectant soap, and wearing of prescribed uniforms.
2. Uniforms usually consist of sterile overalls, hats, facemasks and shoe covers. Sterile rubber gloves also may be required.
3. Uniforms are worn to control emission of particulate matter, which is continually shedding from body surfaces.

Procedures cont…

4. Aware of the hazards, which can be caused by using products of poor standards.
5. Behaviour like smoking, eating, drinking, chewing, attending phone calls, in- and out-movements and any other activity that influence the product quality while in production processes are restricted

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Raw Materials Requirements� for Sterile Production

• All materials purchased for use in compounding and dispensing
1. Should be of suitable quality and obtained from a licensed or reliable source.
2. ‘In house’ check of quality may be made on starting materials.
3. Materials should be fully identifiable and carry a clear batch identification and expiry date.
4. Appropriate storage conditions should be maintained and out-of-date stock safely disposed

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Documentation Requirements �for Sterile Production

• All compounding procedures should be fully documented and the record should include the following details:
1. The name of the product.
2. A written master formula & the working formula of the batch being prepared.
3. The method of preparation
4. The names, quantities and identification of each starting material (supplier, batch number and date received)
5. The date of manufacture.
6. The appropriate container and closure.
7. The required storage conditions.
8. A copy of the label.

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Equipment Requirements �for Sterile Production.

• Equipment requirements for sterile production:
1. Should be of appropriate design,
2. Suitable, well maintained and adequate for the work to be undertaken.
3. All equipment must be maintained in accurate working order
4. Checked for cleanliness prior to each use.
5. Should be simple to use.
6. Should be durable
7. Spare parts should be available
8. Service free
9. Cheap.

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Key Points

• The quality of sterile pharmaceuticals produced will depends very much on the degree of care taken during its preparation; each step in the production process is a possible source of contamination to the manufactured product.
• All materials purchased for use in compounding and dispensing, should be of suitable quality and obtained from a licensed or reliable source, ‘In house’ check of quality may be made on starting materials.
• All compounding procedures should be fully documented and the record should include the details like the name of the product, a written master formula & The working formula of the batch being prepared and the method of preparation the names, quantities and identification of each starting material (supplier, batch number and date received)

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Evaluation

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1. What are premises requirements for sterile production?
2. What are raw materials requirements for sterile production?
3. What are documentation requirements for sterile production?

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end

SESSION 4�Percutaneous Absorption

Learning Tasks

• By the end of this session students are expected to be able to:
1. Explain percutaneous Absorption
2. Explain factors affecting percutaneous absorption

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Percutaneous Absorption

• Percutaneous absorption is the term used to describe the penetration of a substance through the skin and subsequent movement into the systemic circulation

For drugs applied topically for therapeutic purpose, its necessary that:

1. The medicament is released from the base
2. Adequate amount of drug penetrate the skin
3. Sufficient concentration of the drug is maintained at the site of action which will activate the pharmacological response

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Note

• In some instance, skin penetration of medicament is not necessary for a topical applied medicament
• A surface film of the active medicament is necessary for this instance. e.g. for medicament applied topically purposely for:
1. Skin protection (against sunlight or moisture loss
2. For emollient effect
3. For antimicrobial activities in skin disinfection

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Note cont…

• When skin penetration for local activity is the aim, the active substance should be retained for as longer as possible in the viable epidermis and dermis with minimal elimination by systemic circulation.
• Therefore, by regarding skin as the route of drug administration, it’s important to know the mechanism by which medicaments penetrates the skin barrier.

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Functions of the skin

• Regulation of body temperature
• Regulation of blood pressure
• Barrier against damage by radiation, physical action, chemical agents and microorganisms

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Structure of skin

The skin is divided into three layers:

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1. epidermis
2. dermis
3. hypodermis (subcutaneous fat layer)

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Epidermis

• Is about 110µm thick
• Is pierced by hair follicles & sebaceous gland
• It is non vascular
• The outer layer of the epidermis is called stratum corneum
• The stratum corneum is transparent, tough coherent & viscoelastic properties.
• The stratum corneum is composed of dead cells each packed with keratin.

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Epidermis cont…

• Resistance to the diffusion of chemicals is greater in stratum corneum (sc) than in the underlying living skin tissue.
• SC is the rate-limiting barrier to movement of materials & responsible tissue for impenetrability of the skin.
• However the is not an absolute barriers and trace amount of penetrants can be detected; eg nickel, chromium ions, parathion & toxic gases.
• The thickness of sc varies. It is thick on the plantar & palmar areas and thin behind the ear and on the eyelid.

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Epidermis cont…

• Cells are formed through mitosis at the basale layer
• The daughter cells move up the strata changing shape and composition as they die due to isolation from their blood source
• The cytoplasm is released and the protein keratin is inserted.
• They eventually reach the corneum and slough off (desquamation).
• This process is called keratinization and takes place within about 27 days.
• This keratinized layer of skin is responsible for keeping water in the body and keeping other harmful chemicals and pathogens out, making skin a natural barrier to infection.

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Dermis

• The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain.
• The dermis is tightly connected to the epidermis by a basement membrane.
• It also harbours many Mechanoreceptor/nerve endings that provide the sense of touch and heat.
• It contains the hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and blood vessels.
• The blood vessels in the dermis provide nourishment and waste removal from its own cells as well as from the Stratum basale of the epidermis

Hypodermis

• The hypodermis lies below the dermis
• Its purpose is to attach the skin to underlying bone and muscle as well as supplying it with blood vessels and nerves.
• The main cell types are fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of body fat). Fat serves as padding and insulation for the body

Structure of skin

Skin appendages

• Hair follicles
• Sebaceous glands
• Sweat glands

Factors Affecting Percutaneous Absorption

• Factors affecting percutaneous absorption can be considered under three main heading
1. Condition of the skin
2. Physicochemical characteristics of the active substance
3. Effect due to the vehicle

Condition of the skin

• Damage or disease
• Intact skin is a tough barrier
• Damaged or diseased skin is more permeable
• May be damaged by dryness, irritation, allergic reactions or abrasion or UV-radiation, Allergic reaction
2. Injured skin has increased percutaneous than intact skin

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Condition of the skin cont…

• Age
• Percutaneous absorption of infants is higher than in adult to a given medicament due to
• large surface area than that of adult
• Partial developed epidermal drug metabolizing enzymes.
• Old age can also affect permeability of the skin through change in the elasticity, ultra structure, chemical composition & barrier properties

Condition of the skin cont…

• Temperature & humidity;
• Absorption is influenced by environmental factors such as skin temperature & surface humidity,
• Diffusion can be accelerated by raising surface temperature e.g. by occlusion

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Condition of the skin cont…

• Skin site
• Fick’s law of diffusion states that the diffusion of a solute will be inversely proportional to the thickness of stratum corneum.
• In the plantar & palmar the SC is thick & absorption rate is low than in thin thickness like on face & behind the ear.

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Condition of the skin cont…

• Hydration.
• Absorption of active substance is enhanced as the skin become more hydrated.
• Topical medicament with occlusive effect has high absorption rate than the non-occlusive

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Factors associated with the vehicle

• The vehicle may enhance the penetration of a drug in one or more of the following ways:
• By ensuring good contact with the surface of the body.
• By increasing the degree of hydration of the stratum corneum.
• By penetrating the epidermis.
• By directly altering the permeability of the skin.

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Factors associated with physicochemical characteristics of the medicament

1. Molecular modification
2. Drugs solubility and distribution characteristics
3. Particle size
4. Polymorphism
5. Concentration difference of the drug across the membrane

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KEY POINTS

SESSION 5�Semi Solid Preparations

LEARNING TASKS

• By the end of this session students are expected to be able to:
1. Define semi – solid pharmaceutical preparations
2. List ideal properties of semi – solid preparations
3. Explain rational approaches to topical formulation
4. List treatment target for semisolid preparations
5. Explain components of semi – solid pharmaceutical preparations

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Definition of Semi – Solid Preparations

• Pharmaceutical semisolid preparations: Are the topical products intended for application on the skin or accessible mucous membranes to provide localized and sometimes systemic effects at the site of application, it is a preparations designed to exert local activity when applied to the skin or mucous membranes

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Definition of Semi – Solid Preparations

• The main medicinal applications of semi-solids pharmaceutical preparations are as protective, emollient, and therapeutic agents, these semi-solid pharmaceutical preparations for external application are: ointments, pastes, creams, poultices/cataplasms and gels.

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Ideal Properties of Semi – Solid Preparations

1. Physical properties

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• Smooth texture
• Elegant in appearance
• Non dehydrating
• Non gritty/persistent
• Non greasy and non-staining
• Non hygroscopic

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2. Physiological properties:

• Non irritating
• Do not alter membrane / skin functioning
• Miscible with skin secretion
• Have low sensitization index

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3. Application properties:

• Easily applicable with efficient drug release.
• High aqueous washability.

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4. Storage properties:

• Should be stored at temperatures not exceeding 25°c unless otherwise authorized.
• They should not be allowed to freeze and must be stored in a well-closed container or, if the preparation contains water or other volatile ingredients, store in an airtight container.
• The containers are preferably collapsible metal tubes from which the preparation may be readily extruded.
• If the preparation is sterile, store in a sterile, airtight, tamper-proof container.

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Rational Approaches to Topical Formulation

• There are three main methods for a successful formulation of topical dosage form

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Method 1

• By manipulating barrier function of skin;
1. Topical antibiotics help damaged barrier to avoid infections
2. Sunscreen and the horny layer protect viable tissues from u.v. radiations
3. Emollients restore pliability to desiccated horny layer

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Method 2

• By directing drugs to the viable skin tissues without using oral, systemic or other routes of therapy

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Method 3

• By using skin delivery for systemic treatment
• e.g. transdermal therapeutic systems provide systemic therapy for motion sickness, angina and hypertension

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Advantages of Topical Semisolid Preparation

• Easy to apply
• Rapid formulation
• Ability to topically deliver a wide variety of drug molecules
• Provide localized drug delivery
• Explored for systemic delivery of various drug

Types of Topical Semisolid Preparations

• Semisolid preparations are classified according to their flow, adhesion , stiffness and rheology into;

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• Creams
• Gels (Jellies)
• Ointments
• Pastes
• Poultices
• Plasters
• Liniments
• Pessaries
• Suppositories

Treatment Target for Semi – Solid Preparations

• Five main target regions:
• Skin surface, horny layer, viable epidermis and upper dermis, skin glands, and systemic circulation.

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1. Surface treatment

• Care for skin surface is mainly by cosmetic application, that form protective layer, or attack bacteria and fungi
• Sunscreens, barriers that hinder moisture loss, antimicrobials and insect repellants)

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2. Stratum corneum treatment

• Main therapies aimed at the horny layer improve emolliency by raising water content or stimulating sloughing/shedding
• E.g. keratosis, exfolients such as salicylic acid

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3. Skin appendage treatment

• Antiperspirants (aluminium) reduce hyperhidrosis of sweat glands
• Exfolients (e.g. salicylic acid, tretinoin (retinoic acid), benzoyl peroxide) for acne
• Topical antimicrobials, depilatories etc.

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4. Viable epidermis and dermis treatment

• Diseases can be treated provided that the preparation efficiently delivers drug to the receptor
• E.g. anti-inflammatory drugs (steroids & non steroids), antitumor (e.g. methotrexate, 5-fluorouracil) anesthetics (e.g. benzocaine), antihistamines

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5. Systemic treatment via percutaneous absorption

• In recent years considerable scientific work has led to the skin route being used to treat several conditions by means of transdermal patches
• E.g. motion sickness (hyoscine), angina (nitroglycerin)

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Components of Semi – Solid Pharmaceutical Preparations

1. Antioxidant
• Prevents or slows oxidation of other components
• Examples: Tocopherol, butylated hydroxy toluene, or a reducing agent such as ascorbic acid.

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2. Base

• Major classes or types of formulation compositions based on composition and physical properties.
• Examples: Please refer to bases chapter.

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3. Buffer

• Acid-conjugate base mixture employed to control pH and therefore control ionization state of drug and impart stability
• Examples: Citrate, phosphate, tartarate

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4. Chelating agent

• Have the ability to bind metal ions; prevents auto-oxidation phenomena frequently catalyzed by metal ions and enhances action of preservatives by binding iron and copper ions essential to microbial growth.
• Example: EDTA, citric acid

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5. Emulsifying agent

• Reduces surface tension of two phases in an emulsion, preventing coalescence of individual phases.
• Example: Detergent, emulsifying wax (detergent treated wax), cetostearyl alcohol, polysorbate 20.

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6. Humectants

• Promotes retention of water in a mixture Glycerin, propylene glycol, polyethylene glycols (low MW).

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7. Permeation enhancer:

• Facilitates diffusion process of active ingredient across the stratum corneum by chemical modification.
• Example: Ethanol, oleic acid, propylene glycol, polyethylene glycol (400)

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8. Preservative:

• Prevents or slows microbial growth; may be one of 4 major compound types: acid, alcohol, quaternary ammonium compounds, or organic mercurial.
• Example: Acid: benzoic acid; alcohol: phenylethyl alcohol; quaternary ammonium: stearyl dimethyl benzyl ammonium chloride; organic mercurial: thimerosal.

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9. Thickening agent:

• Increase viscosity; may be natural, semi-synthetic, or synthetic.
• Example: Natural: cellulose, pectin; semi-synthetic: methylcellulose, (sodium) carboxymethylcellulose; synthetic: Carbopol

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END

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THANK YOU FOR YOUR ATTENTION:

SESSION 6�Reference and Formula in Pharmaceutical

Learning Tasks

• By the end of this session students are expected to be able to:
1. Define monographs
2. List different types of references used in Pharmaceutical production
3. Identify Formula for Pharmaceutical preparations
4. Reduce or enlarge official formula to obtain required formula for compounding

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Definition of monographs

• A monograph is a specialist work of writing in contrast to reference works on a single subject or an aspect of a subject, often by a single author, and usually on a scholarly subject.
• In library cataloging, monograph has a broader meaning, that of a non-serial publication complete in one volume(book) or a definite number of volumes. Thus it differs from a serial publication such as a magazine, journal , or newspaper

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Types of References Used in Pharmaceutical Production

• British Pharmacopoeia (BP)
• Book of standards of purity and strength for medical substances, products, dressings, etc. together with ‘official’ assays and tests.
• British Pharmaceutical Codex (BPC) 1973
• Provides a source of standards for some extemporaneous preparations not included in the BP and is now incorporated into the Pharmaceutical Codex.

British National Formulary (BNF)

• Provides general guidance for prescribers together with the special requirements of particular groups of patient, e.g. the very young, the elderly, pregnant women and patient with renal or hepatic failure.
• Contains notes on drugs and preparations classified under the diseases and conditions to be treated.
• Information on indications, contraindications, cautions, side effects and doses are given for each drug listed.
• A formulary for commonly used ‘official’ extemporaneous preparations and information on drug interactions, cautionary and advisory labels, etc. for the pharmacists are included.

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Types of References Cont…

• European Pharmacopoeia (EP or Ph. Eur).
• Prepared under the auspices(umbrella) of the council of Europe and was created to permit free circulation of drugs within the European community.

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Types of References Cont…

• Pharmaceutical Codex (PCx) 1979
• The PC is an encyclopedia of drug information and includes entries on diseases and conditions, aspects of pharmaceutics, surgical dressings and veterinary information as well as the formulae for medicines

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Types of References Cont…

• International Pharmacopoeia (IP)
• Publication of the World Health Organization (WHO) providing recommended standards for international use.
• United States Pharmacopoeia (USP) and National Formulary (NF)
• The official standard reference of the United States of America (USA). There is a companion volume of dispensing information (USPDI).

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Types of References Cont…

• Martindale: The Extra Pharmacopoeia
• An authoritative reference book on drugs and medicines in current use throughout the world. Martindale provides detailed information on nomenclature, physical and pharmaceutical properties, adverse effects, actions and uses, etc.

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Types of References Cont…

• Pharmaceutical Handbook
• A reference manual for practitioners and students of pharmacy and the allied professions. Information such as ‘The preparation and supply of medicines’, ‘methods of sterilization,’ ‘nomenclature of organic compounds’, desirable body weights and calculation of body surface areas which are useful data relevant to pharmacy.

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Identification of Formula for Pharmaceutical Preparation

• After comprehended the request in the prescription, a compounder has to identify the correct formula from the reference book
• The correct formulas from the reference book can be obtain through the following ways:
• Find the name of the pharmaceutical preparation to be compounded through table of contents of the reference book and go to formulation, e.g. solution.
• The formulation in the content indicates the page where the respective formula is indicated.
• Find the name of the pharmaceutical preparation to be compounded through the index of the reference book
• The index indicates the number of page where the respective formula is indicated

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Below are official formulas obtained from the reference book (TPH) under the indicated table of content of the book.

• COMPOUND BENZOIC ACID OINTMENTPCx (Syn.Whitfield’s Ointment)
• Benzoic acid, in fine powder…………………6.0 g 
• Salicylic acid, in fine powder…………………3.0 g 
• Emulsifying ointment …………………………91.0g

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Cont…

• SULPHUR OINTMENT PCx.
• Precipitated sulphur, finely sifted……10.0 g
• Simple ointment………………………90.0 g

​

​

• Reduction and Enlarging of Official Formula to Obtain Amount of Each Ingredient Required for Compounding

Cont…

• Reducing and enlarging formula are calculations performed when the required amounts of medicines (Prescribed/ordered) deviate from the official formula in a reference book.
• Obtaining the amount of each ingredient required for compounding, the figures of the official formula are multiplied by a factor which is determined by the following proportion:-

​

To Determine Amount of Each Ingredient Required for Compounding

1. What is the amount of each ingredient required to make 50g of Salicylic acid ointment PCx?
2. What is the amount of each ingredient required to make 20g Compound zinc oxide PCx?

​

Practice

• Practice in the laboratory in identification of formula needed in pharmaceutical compounding from the references book
1. ZINC AND COALTAR OINTMENT (TPH)
2. ZINC AND SALICYLIC ACID PASTE (TPH).
3. PARAFFIN OINTMENT (TPH)
4. EMULSIFYING OINTMENT (TPH)

​

Assignment

• Practice Calculations of amounts required for compounding from the official formula in the following exercise

END

​

​

• THANK YOU FOR YOUR ATTENTION

Compounding of Ointments

Learning Tasks

• By the end of this session students are expected to be able to:
1. Define ointment
2. Describe procedures for preparing ointment
3. Prepare ointment
4. Label prepared ointment
5. Dispense prepared ointment into suitable containers and closure

​

Ointments

• Definition
• Ointments are soft, semi-solid, greasy external preparations for application to the skin and certain mucous membrane
• They are solutions or dispersion of one or more medicaments in non-aqueous bases
• Some ointments are non medicated

​

Ointments

• Uses
• As emollients
• As skin protective
• As vehicle for medicaments intended to produce pharmacological effect at, near or at the site of application

​

Ointments

• Note;
• Because ointments are greasy, sticky and retains sweat,
• They are not suitable in wet weepy dermatitis, hairy areas, skin prone to folliculitis, or hot weather conditions

Ointments

• Application
• Patients are directed to apply ointments to the skin or mucous membrane with inunction
• i.e. rub or smear the ointment into the affected areas, avoiding open wounds

​

Ointments

• Ingredients:
• Drug substance (API) +base (s) ± Adjuvants

​

Classification/types of ointment

• According to Base Used :
1. Hydrocarbon bases,
2. Absorption bases,
3. Water-miscible bases (Emulsifying bases)
4. Water-soluble bases.

​

Classification of Ointments

• According to Use/Therapeutic Classification
• Emollient
• Protective
• Anti Infectives
• Anti Eczematic
• Keratolytic
• Anti Prespirants
• Anti Sebhorrics

​

Classification of Ointments

• According to Penetration
1. Epidermic Ointments
1. Slight penetration power
2. Therapeutic effect on diseased epithelium
3. E.g, containing petrolatum, waxes

​

Classification of Ointments

• According to Penetration
2. Endothermic Ointments
1. Power of deeper penetration
2. e.g, with vegetable oils, lanolin
3. Diadermic Ointments
1. Penetrate skin effectively
2. Better absorption
3. e.g emulsion type & water soluble.

​

Ideal characteristics of �ointment bases

1. should not cause irritation or sensitization of the skin
2. should not retard wound healing process
3. should be smooth
4. should be inert; i.e. no pharmacological effect
5. should be odourless
6. should be physically and chemically stable
7. should be compatible with the skin and with other dermatological medicaments

Hydrocarbon Bases Cont…

• The members of this group have the following characteristics:

(a) They are not Absorbed by the Skin�They remain on the surface as an occlusive layer that restricts loss of moisture and keep the skin soft, but may lead to water-logging with consequent maceration of the skin, if application is prolonged.

• Retains body heat, which may produce an uncomfortable feeling of warmth.
• They do not aid the absorption of medicaments, hence are used mainly for their protective and emollient effects or when superficial medication is adequate.

Hydrocarbon Bases Cont…

(b) They are Immiscible with Water

• The rubbing into the surface and removal after treatment are difficult.

(c) They are Sticky

• This ensures prolonged contact between skin and medicament but makes application unpleasant and leads to contamination of clothes.

(d) They are almost inert �They consist largely of saturated hydrocarbons; therefore have very few incompatibilities and little tendency to rancidity.

• They are suitable for sterile products because they are stable to dry heat sterilisation.
• Instances of skin sensitisation are rare and, as they rarely encourage the growth of micro-organisms, an antimicrobial preservative is unnecessary.

Hydrocarbon Bases Cont…

• (e) Water Absorption is Low

​

• They absorb very little water from a formulation or from skin exudates.
• However, they inhibit water loss from the skin by forming a waterproof film and by improving hydration, may encourage absorption of the medicaments through the skin.
• Therefore, they are most suitable for conditions in which the skin is dry.

​

• (f) Their constituents are readily available and cheap.

​

Hydrocarbon Bases Examples

• Soft paraffin e.g yellow soft paraffin and white soft paraffin.
• Hard paraffin
• Paraffin substitute
• Liquid paraffin

​

Absorption Bases

• Absorption bases, unlike the hydrocarbon type, are hydrophilic and can absorb considerable amounts of water or aqueous solutions.
• Examples
• Hydrous Wool Fat BP (lanolin)
• Oily Cream BP.
• Wool alcohols,
• Beeswax
• Cholesterol.

​

​

​

Water miscible Bases �(Emulsifying bases)

• These bases contain oil-in-water (o/w) emulsifying agents which render them readily miscible with water or ‘self-emulsifying’.
• Ointments made from water-miscible bases are easily removed after use.

​

EXAMPLES

Advantages of using water-miscible bases/ emulsifying bases regularly are:

• They are miscible with exudates from lesions
• Reduced interference with skin functions
• They have good contact with the skin because of their surfactant content
• They have high cosmetic acceptability; hence there is less likelihood of the patient discontinuing treatment
• Can be easily removed from the hair and hence they are useful for preparing scalp ointments.
• Ointments with hydrocarbon or absorption bases are not very suitable for scalp conditions because their removal is unpleasant and difficult.

​

Disadvantages of water soluble bases

• Limited uptake of water

​

• Less bland than paraffins: possibly due to their hygroscopic nature.

​

• Reduction in activity of certain antibacterial agents, e.g. �phenols, hydroxybenzoates and quaternary ammonium compounds. Penicillins and Bacitracin are rapidly inactivated

​

• Solvent action on polythene and bakelite. �These plastics should not be used in containers or closures for macrogol ointments.

Criteria for Selection of ointment base

(1) the site of application;

(2) properties of the active pharmaceutical

Ingredient( API)such as known solubility in hydrophobic or hydrophilic vehicles;

(3) release of API from the formulation into the applied area;

(4) the need for a moisture barrier;

(5) the indication itself, as it may have marketed products with which it needs to be competitive

Describe Procedures for Preparing Ointments

• Basic Techniques for Preparation
• Weighing
• Measuring liquids
• Size reduction
• Size separation (sieving)
• Mixing (Fusion or Trituration)

Ointments

• Methods of Preparation
• Trituration (Incorporation) Method
• Fusion Method
• Emulsification Method

​

Method used depends on;

• Properties of the medicaments
• Type of basis
• Quantity of ointment required

​

Trituration (Incorporation) Method

• Used when medicament to be incorporated is insoluble in the ointment base or a liquid present in small amount
• Involves incorporation of drug by levigation
• Used for small quantities of relatively soft ointment
• Ointment tile and spatula or mortar & pestle may be used

Trituration (Incorporation) Method Cont…

​

• Employs a slab and a spatula of flexible metal or plastic for mixing and incorporation of liquids or solids
• Steel spatula are suitable for most substances but should not be used for ointments containing Hg salts, tannic acid, salicylic acid or iodine

Trituration (Incorporation) Method Cont…

• Insoluble solids must be finely powdered and sieved (250um/180um/125um mesh)
• Sifted powder is then levigated with some of melted base or other a suitable liquid
• Wool fat, gylcerol are good levigating agents

​

Trituration (Incorporation) Method Cont…

• Water soluble salts should be dissolved in minimum amount of water and then incorporated with aid of small amount of lanolin
• Mortar and pestle is used if liquids are used for larger quantities of ointment

​

Trituration (Incorporation) Method Cont…

• After levigation or dissolution the concentrate is diluted geometrically with the base, with scrapping off of material from the sides of the mortar and pestle
• Trituration is done until the preparation is uniform

​

Fusion Method

• Used for large-scale manufacturing or for ointments in which waxes or solids or high melting points are mixed with semi-solids or oils
• Also used when large volume of water are to be incorporated

Fusion Method Cont…

• Constituents are melted successively in decreasing order of MP
• The fluid mixture stirred until cooled, avoiding aeration
• Crystals of fatty alcohols form (in systems with paraffins) if not well stirred

​

Fusion Method Cont…

• Volatile medicaments are added when ointment has cooled below 40⁰C
• Insoluble powders in form of levigated dispersion are incorporated when ointments begin to thicken
• Soluble, heat-stable can be dissolved in melted basis before congealing thickening
• Roller mills or colloid mills may be used to improve homogeneity to attain uniform distribution of insoluble solids and elimination of larger particles

​

​

Emulsification Method

• Employed in preparation of ointments with an emulsion type of formula
• Involves a melting process and an emulsification process.
• water-immiscible components e.g. the oil and waxes are melted together in a steam bath to about 70 to 75°C

​

​

Emulsification Method Cont…

• Meantime, an aqueous solution of all heat-stable, water-soluble components is being prepared in the amount of purified water specified in the formula and heated to the same temperature as the oleaginous (greasy) components

Emulsification Method Cont…

• Then the aqueous solution is slowly added, with constant stirring (usually with a mechanical stirrer), to the melted oleaginous mixture, the temperature is maintained for 5 to 10 minutes to prevent crystallization of waxes

​

Emulsification Method Cont…

• The mixture is slowly cooled with the stirring continued until the mixture is congealed.
• If the aqueous solution were not at the same temperature as the oleaginous melt, there would be solidification of some of the waxes on addition of the colder aqueous solution to the melted mixture.

​

Dilution of Ointment

• Dilution of stronger ointment is done when strength prescribed is not available
• Only recommended diluents should be used e.g. soft paraffin

​

​

Dilution of Ointment Cont…

• In tropical climates, the bases that are too soft are stiffened by addition of fats, hard paraffin, or waxes
• This addition is permitted if active ingredients content or action is not altered

Preparation of Ointment

• In preparation of ointments every official formula has got its procedures on how to carry out the preparation, although the general procedures remain as mentioned on above.

​

Note

• REFER to the official formula of preparing calamine ointment PCx In the Tanzania Pharmaceutical Handbook
• DEMONSTRATE the procedure of preparing ointments according to the instruction under the official formula in the Tanzania Pharmaceutical Handbook (Mitte 50g)

​

Official formula given for calamine ointment PCx

• Calamine, finely sifted………………….15.0g
• White soft paraffin………………… …85.0g

​

• Mitte 50.0g for Anna Juma

​

Cont…

Then, amount of each ingredient can be obtain as summarised in the table below:

Method of preparation

1. Weigh 7.5g of calamine, finely sifted
2. Transfer the weighed ( 7.5g) of calamine, finely sifted into a mortar
3. Weigh 42.5g of white soft paraffin
4. Add to the powders about two or three times their weight of white soft paraffin
5. After each addition trituration should be done for 3 to 5 minutes
6. Triturate until it is completely uniform
7. Then transferred to suitable container, label and ready for dispensing to a patient.

​

Labeling of Prepared Ointment

• Container should be labeled;
• “For External Uses Only” (red) and “Store at a Cool Place” when appropriate
• Strength of active ingredient should be given as % w/w, (or %v/v) or %w/v
• If diluted product should indicate,“Should Not be Used Later than Two Weeks After Issue” unless otherwise stated
• If preserved, name and concentration should appear on the label
• Is sterile, should be labeled “Sterile”

​

Important things required to appear on the label.

​

• The name (underlined) and quantity of the preparation
• The patient’s name
• The date of dispensing (preparation date)
• Dose and instruction for use.
• The expiry date, where applicable and/ or manufacturing date
• Storage condition
• The name of the dispenser (initial)
• The name and address of the dispensing institution.
• Required dispensing information, such as Shake well before use.

​

Example of labels:

Dispensing of Prepared Ointment into Suitable Containers and Closure.

​

• What are suitable containers and closure for ointments?

​

Containers

• Well-closed containers
• Container should prevent evaporation
• Should prevent contamination of contents
• Should not release or absorb/adsorb anything from the contents=
• Flexible plastic tubes or
• Collapsible metal tubes
• Wide-mouth glass or plastic jars with plastic screw caps with impermeable liners or close fitting slip-on lids

​

Note:

• Check for reaction between container material and contents before making choice of containers

​

Ointment jars.

Ointment Containers

END

Compounding of Pastes

Learning Tasks

• By the end of this session students are expected to be able to:
1. Define paste
2. Describe procedures for preparing paste
3. Prepare paste
4. Label prepared paste
5. Dispense prepared paste into suitable containers and closure

​

Pastes

• Definition
• Pastes are external semi-solid preparations containing large proportions (20% -60%) of solids finely dispersed in the basis
• Pastes are like ointments but contain more solid materials and are stiffer
• Pastes are basically ointments into which a high % of insoluble solid has been added

​

199

Types of Pastes

​

• There are two types of paste:
• Fatty pastes e.g.: Lassar's paste
• Non greasy pastes e g: Bassorin paste
• Examples of pastes
• Coal tar paste P.CX (astringent, antipruritic)
• Compound zinc paste P.CX (astringent)
• Zinc and Salicylic acid Paste P.CX (Lassar’s paste) astringent

​

​

200

Pastes

• Characteristics
• Contain more solids than ointments
• Are stiffer than ointments
• Are less greasy than ointments
• Are less occlusive than ointment
• This is because of high porosity caused by high powder content
• Cause less maceration of the skin

201

Characteristics of Pastes

• Are more absorbent to exudate weeping lesions
• Pastes are less penetrating and less macerating and less heating than ointment

202

NOTE

• Like ointments,
• Paste forms an unbroken relatively water – impermeable film
• Unlike ointments,
• Film formed by pastes is opaque, thus can be used as an effective sun block accordingly.

​

​

Pastes

• Uses
• Used principally as;
• Absorbents
• Antiseptics
• Protectives or
• Soothing dressings for broken skin surfaces
• Usually pastes are used for small localized areas of the skin

204

Pastes

• Application
• Applied thickly on dressings such as gauze (rather than directly on the skin)
• This is because of their thick consistency
• Bases
• Base materials (hydrocarbon or water-miscible) for preparation of pastes include soft paraffin, liquid paraffin, glycerol, mucilages, emulsifying waxes and Ointments

205

Describe Procedures for Preparing Pastes

• weighing,
• measuring liquids,
• size reduction,
• size separation (sieving) and
• mixing (Fusion or Trituration),

Pastes

• Preparation
• More less like ointments
• E.g. Compound Zinc Paste P.CX (Syn Zinc Paste)
• Zinc oxide, finely sifted ……………….. 25.0g
• Starch, finely sifted……………………….25.0g
• White soft paraffin……………………….50.0g
• The powders are triturated with the melted soft paraffin

​

​

​

​

207

Official formula given for compound zinc paste PCx

​

• Zinc oxide, finely sifted……………25.0g
• Starch, finely sifted…………………25.0g
• White soft paraffin…………………50.0g
• Mitte 50.0g for Alex Shabani

​

Method of preparation

• Weigh 12.5g of Zinc oxide, finely sifted and 12.5g Starch, finely sifted
• Transfer the weighed ( 12.5g) of Zinc oxide, finely sifted and Starch, finely sifted into a mortar
• Weigh 25.0g of white soft paraffin
• Add to the powders about two or three times their weight of melted white soft paraffin
• After each addition trituration should be done for 3 to 5 minutes
• Triturate until it is completely uniform
• Then transferred to suitable container, label and ready for dispensing to a patient.

​

Labeling of Prepared Paste

• Labeling
• As for ointments

​

Dispensing of Prepared pastes into Suitable Containers and �Closure.

​

• Containers
• As for ointments
• Pastes tubes of metal or plastic or in wide-mouthed jars of glass or plastic

​

Paste jars and tube

Evaluation

• What are pastes?
• What are procedures for preparing pastes?
• What are suitable containers and closure for pastes?

​

​

Compounding of Creams

Learning Tasks

• By the end of this session students are expected to be able to:
1. Define creams
2. Describe procedures for preparing creams
3. Prepare creams
4. Label prepared cream
5. Dispense prepared cream into suitable containers and closure

​

Definition of Creams

• Creams are semi-solid emulsions intended for application to the skin or mucous membrane, they are viscous semisolid emulsion system with opaque appearance

​

Usually they are of two types, namely:

1. Aqueous creams, i.e. oil-in-water emulsions. This creams contain oil-in-water emulsifying agent
2. Oily creams, i.e. water-in-oil emulsions. This cream contain water-in-oil emulsifying agent.

​

Differences Cont…

Differences Cont…

• Aqueous creams are relatively non-greasy and are most useful as water-washable bases whereas oily creams are emollient and cleansing.
• Patients often prefer a w/o cream to an ointment because the cream spreads more readily, is less greasy and the evaporating water soothes the inflamed tissue.�

• O/w creams (‘vanishing’ creams) rub into the skin; the continuous phase evaporates and increases the concentration of a water-soluble drug in the adhering film. �
• Consistency and rheological characters depend on weather the cream is w/o or o/w.
• Creams intended for application to large open wounds should be sterile.

​

Creams

• Uses
• For applying solution or dispersion of medicament to the skin for therapeutic or prophylaxis where highly occlusive effect is not necessary i.e. as nonoclusive vehicles
• Plain creams are used for following effects on the skin;
• Emollient
• Cooling
• Moisturizing

226

Application

• Are applied by smearing smoothly to the skin and leave a very thin film

​

Ingredients Used in Creams

• Stabilizers
• Finely divided solids e.g. bentonite
• Thickening agents
• Increase stability & viscosity e.g. Microcrystalline wax, Spermaceti, Paraffin wax etc.
• Preservatives: e.g. Paraben derivatives

​

228

Ingredients Used in Creams

• Antioxidants
• Neutralize free radicals which mediate many forms of inflammation
• Antioxidants reduce skin's exposure to free radicals
• It also prevent the oxidation of the oil phase.
• E.g. Vit E etc

229

Ingredients Used in Creams

• Base/vehicle
• The base that carries the active ingredients
• E.g. Hydrophilic petrolatum, Anhydrous lanolin, Mineral oil, Sesame oil etc

230

Procedures for Preparing Creams

1. Emulsified creams are prepared by heating the components of the oily phase including the emulgent until molten and then cooling to 60°C.
2. The components of the aqueous phase are mixed in a separate vessel and also heated at 60°C.
3. The aqueous phase is then added to the oily phase at the same temperature, this is very important and the thermometer should be used.

​

• The resulting emulsion should be stirred until cool.
• Rapid cooling may result in separation of high melting point components and excessive aeration caused by vigorous stirring may also lead to a granular product.
• If necessary the product may be homogenized after cooling.

​

Dilution of creams

• Should be done under hygienic conditions
• Stability and bactericidal properties of original cream should NOT be reduced on dilution
• The diluent should be compatible with ingredients and the whole original preparation
• Dilution may alter extent of release of medicament from creams
• Information on suitability of diluent should be available, otherwise DO NOT DILUTE

​

Preservation & hygiene during preparation

• Creams can support growth of micro-organisms, hence most need preservatives
• Accidental contamination will almost certainly occur during bench scale manufacture, but good technique can keep this to a minimum
• All apparatus and final containers should be thoroughly cleansed before use and purified water should be used in the preparation of products

​

Preparing of Creams

• DEMONSTRATE the procedure of preparing cream according to the instruction under the official formula in the Tanzania Pharmaceutical Handbook (Mitte 50g)

​

Method of preparation

1. Melt oily phase (heat up to 75^oC, and cool to 60^oC)
2. Prepare aqueous phase and heat to 60^oC
3. Add aqueous phase to oily phase with slow but constant agitation until cold
4. Incorporate insoluble medicinal ingredient
5. Then transferred to suitable container, label and ready for dispensing to a patient.

​

Labeling of Prepared Creams

• The preparation should be labelled “For External Use Only” in red ink and bear the instructions that it should be stored in a cool place.
• The strength of active ingredients must be stated as percentage by weight or by volume.
• For diluted creams, the label should state that the product should not be used after two weeks from the date it was dispensed unless otherwise stated.

​

Labeling of Prepared Creams cont…

• The date of dispensing (preparation date)
• Instruction for use.
• The expiry date, where applicable and/ or manufacturing date
• Storage condition
• The name of the dispenser (initial)
• The name and address of the dispensing institution.

​

Dispensing of Prepared Creams into Suitable Containers and �Closure.

• Creams should be dispensed in well-closed containers to prevent evaporation of the aqueous phase.
• Wide-mouthed squat jars may be used for creams where the risk of contamination may be minimal but the mouth of the jar should be covered with a disc of greaseproof paper.
• Collapsible metal or flexible plastic tubes are to be preferred since these reduce the risk of contamination during use, most creams are packed in tubes.

​

Figure 9.1: Cream jars and tube

Key Points

• Creams are semi-solid emulsions intended for application to the skin or mucous membrane, they are viscous semisolid emulsion system with opaque appearance 
• Usually they are of two types, namely: aqueous creams, i.e. oil-in-water emulsions this creams contain oil-in-water emulsifying agent and oily creams, i.e. water-in-oil emulsions, this creams contain water-in-oil emulsifying agent. 
• Suitable containers and closure for creams are: Flexible plastic tubes or collapsible metal tubes and wide-mouth glass or plastic jars with plastic screw caps with impermeable liners or close fitting slip-on lids

​

Evaluation

1. What are creams?
2. What are procedures for preparing creams?
3. What are suitable containers and closure for creams?

​

Compounding of Gels/ Jellies

Learning Tasks

• By the end of this session students are expected to be able to:
1. Give overview of gels
2. Describe procedures for preparing gels
3. Prepare gels
4. Label prepared gels
5. Dispense prepared gels into suitable containers and closure

​

Introduction to Gels

• Gels are transparent (or translucent) semi-solid or solid preparations of either suspensions made up of small inorganic particles or large organic molecules interpenetrated by a liquid
• Are semisolid systems consisting of dispersion of small or large molecules in an aqueous liquid vehicle rendered jelly-like through addition of a gelling agent
• Movement of dispersing system is restricted by interlacing network of particles or solvated macromolecules of dispersed phase

​

Introduction to Gels cont…

• Gels are made using substances (called gelling agents) that undergo a high degree of cross-linking or association when hydrated and dispersed in the dispersing medium or when dissolved in the dispersing medium
• Cross-linking or association of dispersed phase alters the viscosity of the dispersing medium
• Hence the movement of dispersing medium is restricted by the dispersed phase

​

Introduction to Gels cont…

• Two-phase System Gel
• Is when the gel contains a network of small discrete particles
• Two-phase system gels are thixotropic
• Gel mass consists of floccules of small distinct particles
• Usually involve inorganics
• Semisolid on standing but liquefy on shaking
• If the particles in the two-phase systems are large

​

​

​

Introduction to Gels cont…

One or Single-phase System Gel

• When gels appear to have no discrete particles,
• Macromolecules are uniformly distributed throughout the liquid, usually organics
• No apparent boundaries between dispersed macromolecules and the liquid

​

Introduction to Gels cont…

• The gel is called a Magma or Milk
• Composition of gels is:
1. Gelling agents
2. Water
3. Co-solvents
4. Preservatives
5. Stabilizers

​

Introduction to Gels cont…

• One-phase gels are made from synthetic or natural organic macromolecules distributed uniformly throughout a liquid without any boundary between dispersed and dispersing phases (e.g. tragacanth, cellulose, methylcellulose)
• If made from natural gum, single-phase gels are called Mucilages

​

Some Gelling Agents

• Acacia, tragacanth, Methylcellulose,
• Alginic acid, Bentonite, Carbopol®,
• Carboxymethylcellulose (CMC),
• Gelatin, Hydroxypropyl cellulose,
• Magnesium Aluminium Silicate (Veegum®) etc
• Characteristic Properties of gels are:often non-greasy, smooth, elegant, produce cooling effect on application and easily washable from skin 

​

Procedures for Preparing Gels

• Specific method depends on gelling agent e.g. gelatin gels
1. By dispersing gelatin in hot water followed by cooling OR
2. By wetting gelatin with organic liquid e.g. Propylene glycol, followed by addition of hot water and cooling

Example of a gel formulation:

• Methylcellulose and Carbomer Gel Base
• Methylcellulose, 4000cps 1.0%
• Carbomer 934 0.35%
• 1N Sodium Hydroxide Solution qs to pH 7
• Propylene glycol 16.7%
• Methyl paraben 0.015%
• Purified water, qs 100

​

Procedures

• Disperse the methylcellulose in a portion of hot (80-90°C) water
• Cool to room temperature, and disperse the Carbomer 934 in the gel using a bladed stirrer.
• Adjust the pH of the dispersion to 7.0 by adding sufficient 1N Sodium hydroxide solution.
• Dissolve the methylparaben in the propylene glycol. Mix the methylcellulose, Carbopol 934 and propylene glycol fractions using caution to avoid incorporating air.

​

Preparing of gels

• DEMONSTRATE the procedure of preparing Ichthammol gel according to the instruction under the official formula in the Tanzania Pharmaceutical Handbook (Mitte 50g) 

​

Official formula given for Ichthammol gel PCx

• Ichthammol……………………………………1.0g
• Tragacanth, in powder………………………2.5g
• Alcohol 90%…………………………………5.0g
• Glycerin……………………………………1.0g
• Purified water q.s…………………………50.0g

​

• Mitte 50.0g for Allen Mbogo

​

Then, amount of each ingredient can be obtain as summarised in the table below:

Procedure:

• Prepare Ichthammol solution:
• According to solubility,
• 1g Ichthammol 10ml water

​

Procedure cont…

• Formula for Ichthammol solution:
• Ichthammol 1.0g
• Glycerol 1.0g
• Water 10ml

​

Procedure cont…

• Weigh empty beaker (preferably plastic) and weigh1.0g of Ichthammol and 1.0g of glycerol directly into beaker. Add about 10ml of water then stir until obtaining solution.

​

Procedure cont…

• Prepare mucilage:
• Calculate amount of water
• Final weight of jelly – other ingredients.

50g – (1.0g+2.5g+5.0g+1.0g)

​

Procedure cont…

• Ichthammol Tragacanth Alcohol Glycerol (Approximate Conversion)

=50g – 9.5g =40.5g – 40g =40ml water used in preparation

• 10ml water has been used for Ichthammol solution
• 40ml – 10ml=30ml: Amount of water can be used for mucilage.

​

Formula for mucilage

• Tragacanth 2.5gm
• Alcohol (90%) 5.0mL
• Water 30mL
• Weigh2.5g of Tragacanth and measure 5.0ml of alcoholand
• 30ml of water.
• Place alcohol first in mortar and add Tragacanth onto alcohol then disperses by pestle.
• After obtaining uniform dispersion, add water as quickly as possible at once then mix well.
• NB: Alcohol should be placed first otherwise may lead lump formation

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Combine:

• Add Ichthammol solution into the mucilage in portion triturate frequently scraping off the material from the side soft hemortar and the pest leuntil obtaining completely uniform mixture

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Adjust final weight:

• Weigh the empty dispensing container, then transfer jellies into the container.
• Make the required weight by rinsing the mortar and pestle with a small amount of water.
• When the weight is made up, mix the contents well by stirring rod
• Make sure that the product is uniform

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Labeling of Prepared Gels

• As for other external semisolids or otherwise stated

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Example of labels:

Dispensing of Prepared Gels into Suitable Containers and Closure.

• Containers containing gels should be well filled to minimise evaporation of water
• Well closed and stored in a cool place to prevent drying out
• Collapsible tubes should be used for packing the sterile products such as catheter

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Figure : Gels jars and tube

Evaluation

1. What are gels?
2. What are procedures for preparing gels?
3. What are suitable containers and closure for gels?

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Introduction to Isotonicity

Learning Tasks

• By the end of this session students are expected to be able to:
• Give overview isotonicity
• Explain the importance of isotonic solution.
• Effects of administering paratonic solutions

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Introduction to Isotonicity

• When two solutions of different strength are separated by semi permeable membrane which allows only solvent particles but not solute particles to pass through, there will be a movement of solvent particles from the weaker solution towards the stronger solution with the tendency to produce two solutions of the same strength

Introduction cont…

• This means the volume on the side of the stronger solution will increase. This phenomenon or process is called osmosis and the force which causes this movement is called osmotic pressure

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Schematic for osmotic pressure

Introduction cont…

• Body fluids e.g. blood plasma have certain quantity of dissolved substances e.g. salts that determine power of the blood called osmotic pressure. 
• Osmotic pressure is the pressure created by solvent molecules moving from a low concentrated solution to higher concentrated solution through a semi-permeable membrane, a semi-permeable membrane allow only the solvent molecules to pass.

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Introduction cont…

• The characteristics of a solution is determined by the number of dissolved substances in it, aaqueous solutions which exert the same osmotic pressure as blood plasma are said to be isotonic with plasma. This is equivalent to 0.9%w/v sodium chloride injection (Normal saline)

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• If the solute is a non electrolyte, its solution contains only molecules and the osmotic pressure varies with the concentration of the solute.

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• If the solute is an electrolyte, its solution contains ions and the osmotic pressure varies with both the concentration of the solute and its degree of dissociation. Thus, solutes that dissociate present a greater number of particles in solution and exert a greater osmotic pressure than un dissociated molecules.

An isotonic solution

• An isotonic solution is a solution in which body cells can be bathed without a net flow of water across a semi permeable membrane. E.g. 0.9% normal saline (NS).

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Osmolality

• A unit of measure of osmotic pressure.
• Blood has 300 mOsmol per liter. (MiliOsmolality)
• Both Normal Saline and Dextrose 5% solutions have a similar osmolarity.

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• Solutions, which exert a different osmotic pressure as blood plasma, are said to be paratonic with plasma. (i.e. solutions with hypotonic or hypertonic osmotic pressure)
• Those solutions with a lower osmotic pressure than blood plasma are said to be hypotonic solutions and a solution of less than normal tonicity is hypotonic, which has fewer numbers of dissolved solutes than blood cells. E.g. 0.45% Saline. ( <NS)

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Introduction cont…

• Solutions with a higher osmotic pressure than blood plasma are said to be hypertonic solutions, a hypertonic solution has more number of dissolved solutes than the blood cells themselves. E.g. 50% Dextrose or 3% Sodium chloride.

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• Aqueous solutions intended to contact with body fluid should preferably be made isotonic with specific bodily fluid in order to minimize any possible adverse effects.

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• Tonicity is generally classified in three types:
1. Hyper tonicity
2. Hypo tonicity
3. Isotonicity

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1. Isotonic

• Iso - means same/equal
• Tonic means concentration of a solution
• The cell has the same concentration on the inside and outside which in normal conditions the cell’s intracellular and extracellar are isotonic
• It is important to be familiar with what fluids are isotonic and when they are given

Isotonic fluids

• 0.9% Saline
• 5% dextrose in water ( D5W)
• Lactated Ringer’s
2. Isotonic solutions are used to increase the EXTRACELLULAR fluid volume due to blood loss, surgery, dehydration, fluid loss that has been lost extracellularly

2. Hypotonic

• Hypo – mans under/beneath
• Tonic – concentration of a solution
• The cell has a low amount of solute extracellulary and it wants to shift inside the cell to get everything back to normal via osmosis . This will cause CELL SWELLING which can cause the cell to bust or lyses. This process is irreversible

Hypotonic fluids

• 0.45% Saline ( ½ NS)
• 0.225% Saline ( ¼ NS)
• 0.33% Saline ( 1/3 NS)
2. Hypotonic solutions are used when the cell is dehydrated and fluids need to be put back intacellularly . This happen when pts develop hyperglycemia

3. Hypertonic

• Hyper- means excessive
• Tonic – means concentration of a solution
• The cell has an excessive amount of solute extracellularly and osmosis is causing water to rush out of the cell intracellularly to extracellulary area which cause the CELL TO SHRINK.

Hypertonic solutions

• 3% Saline
• 5% Saline
• 10% dextrose in water ( D10W)
2. When hypertonic solutions are used very cautiously most likely to be given in the ICU due to quickly arising side effects of pulmonary edema/fluid over load.

NB:

• Certain paratonic solutions need to be isotonic with body fluids when they are administered . This is achieved by adding some pharmacologically inert solute to hypotonic solutions or by diluting hypertonic ones so that they become iso- osmotic with body fluids
• Like the depression of freezing point, the rising of boiling point and lowering vapor pressure, the osmotic pressure is dependant on the concentration of solute particles in the solution. As it is difficult to measure the osmotic pressure directly, it can be determined indirectly by using e.g the freezing point depression, as both are dependent on the number of solute particles in solution.

Isotonicity & route of administration

1. Subcutaneous injection:
• not necessarily “small dose” but isotonicity reduce pain.
2. Hypodermoclysis
• should be isotonic “Large volume”
3. Intramuscular injection
• should be isotonic or slightly hypertonic to increase penetration
4. Intravenous injection
• should be isotonic “Large volume ”
• Hypotonic cause haemolysis
• Hypertonic solution may be administered slowly into a vein
• Hypertonic large volume administered through a cannula into large vessels.

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Isotonicity & route of administration cont…

5. Intrathecal injection
• Should be isotonic
6. Eye drops
• Rapid diluted by tear, but most of it is isotonic to decrease irritation
7. Eye lotions
• Preferably isotonic
8. Nasal drops
• Isotonic, but not essentially

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• There are different methods to calculate the amount of adjusting substance to be added to hypotonic they are based on freezing point depression , sodium chloride equivalent , molar concentration or millequivalents
•  In pharmacy, isotonicity calculations are most often performed for parenteral and ophthalmic solutions, which must have a freezing point depression of ­0.520C for them to be isotonic with blood plasma and tears. Therefore a solution is considered to be isotonic if it has a freezing point of -0.520C

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Importance of isotonicity

• It is important for a solution to be isotonic with a bodily fluid to prevent irritation and cell damage, and to maximize drug efficacy. Its neutrality is not affecting the osmotic pressure of a cell
• This state allows for the free movement of water across the membrane without changing the concentration of solutes on either side.
• Isotonic solutions are used in Oral Rehydration Therapy (ORT), which is a treatment for dehydration associated with gastroenteritis. ORT replenishes the body's lost electrolytes and promotes the uptake of glucose and fluid by the intestinal epithelial cells.

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Importance of isotonicity cont...

• Isotonic solutions given intravenously in case of severe dehydration and is used in the treatment of hypernatremia (a condition in which serum concentration of sodium is high) in individuals who have impaired water excretion, eg 0.9% NaCl solution
• It can be used as a medium for intravenous administration of drugs like propofol, which are not absorbed well by the intestinal lining.

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Importance of isotonicity cont...

• Isotonic solution used as mediums for dissolving drugs that are used for nebulization (administration of drugs in the form of aerosol), such as ipratropium or salbutamol, eg:�0.9% NaCl or 0.14% H₂CO₃ solutions
• It can be used as an aqueous medium for making many medicines that are administered through the ocular routes such as rinse, eye drops, steroids, antihistamines, antibiotics, etc

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Importance of isotonicity cont...

• They are used in the treatment of conditions like hypovolemia (a condition in which blood volume is lowered either due to injury or other reasons) and acidosis (a condition in which the acidity of the blood increases), eg Lactated Ringer's solution and Hartmann's solution

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Other points on importance of isotonicity

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• Please refers toTanzania Pharmaceutical Handbook pg. 33-50

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Figure: Important of Isotonic solution

Effects of Administering Paratonic Solutions

Intravenous injections

1. Effects of hypotonic solutions on blood-cells:
• When hypotonic solution is injected into the blood stream, blood cells swell rapidly and burst, i.e. the solution cause haemolysis of blood cells particularly if the solution is very hypotonic or a large volume of less hypotonicity.
• This damage is irreversible and dangerous if a large number of cells are involved.

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Intravenous injections cont…

2. Effects of hypertonic solutions on blood-cells
• When hypertonic solution is injected into the blood stream, water passes outwards from blood cells and they shrink, becoming crenate (curved/bent), blood cells returns to normal shape when osmotic pressure becomes normal.
• Therefore, grossly hypertonic solutions may be administered without damage to blood cells, thus injections, which are hypertonic, are slowly injected intravenously to ensure rapid dilution in the blood stream and minimal crenulations of the blood cells.

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Figure : Types of tonicity solutions

Figure : Schematic representation of erythrocyte behavior in tonicity solutions

Figure : Schematic representation of erythrocyte behavior in tonicity solutions

Classes of adjustment of isotonicity

• Class I
• Adding substance to lower f.p of solution to -0.52º
• Freezing point depression (FPD) “cryoscopic method”.
• NaCL equivalent method.
• Class II
• Adding H2O
• White –Vincent method

Key Points

• Body fluids e.g. blood plasma have certain quantity of dissolved substances e.g. salts that determine power of the blood called osmotic pressure. 
• Osmotic pressure is the pressure created by solvent molecules moving from a low concentrated solution to higher concentrated solution through a semi-permeable membrane, a semi-permeable membrane allows only the solvent molecules to pass.

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Key Points cont...

• Tonicity is a measure of the osmotic pressure of two solutions separated by a semi-permeable membrane, it is important for a solution to be isotonic with a bodily fluid to prevent irritation and cell damage, and to maximize drug efficacy. 

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Determination of Isotonicity by Freezing Point Method

Learning Tasks

• By the end of this session students are expected to be able to:
• Give overview of freezing point depression
• Determine the isotonicity by freezing point depression

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Freezing Point Depression

• The freezing point of body fluid is at – 0.52⁰C.
• Any solution freezing at – 0.52⁰C will have the same osmotic pressure as body fluids
• Hypotonic solution will have a higher freezing-point and consequently need the addition of adjusting substance to reach a freezing point of – 0.52⁰C

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Table of freezing point Depressions of 1% w/v Aqueous solutions of commonly Used substances

The amount of adjusting substance which is often sodium chloride, is calculated as shown in the following examples.

• Solution A freezes at – 0.390C. How much sodium has to be added to obtain an isotonic solution?
• The adjusting substance sodium chloride has to decrease the freezing point by 0.52 – 0.39 = 0.13⁰C
• A 1 % w/v sodium chloride solution freezes at – 0.576⁰C; so the amount needed is found by the proportion:

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Calculation cont…

• Therefore, solution A will need the addition of 0.2%w/v sodium chloride in order to become isotonic with body fluids; e.g. 50mL of this solution require 0.1g sodium chloride.

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From the above used proportion, the following equation has been derived:

Example:

• Adjust 1000mL of a 2%w/v solution of anhydrous dextrose isotonic with body fluids; adjusting substance is sodium chloride

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Solution

Determining the Isotonicity by freezing Point Depression

• To determine amount of ingredients required to make isotonic solution

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Group Discussion

• Render the following solution iso – osmotic with blood and tears
• Ephedrine hydrochloride………………0.1g
• Chlorbutol……………………..………0.1g
• Water for preparation…………….to 20mL
• Adjusting substance is sodium chloride

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Solution

Key Points

Assignment

• Calculate the strength of sodium chloride solution which is iso- osmotic with blood serum and tears

Determination of Isotonicity by Sodium Chloride Equivalent Method

Learning Tasks

• By the end of this session students are expected to be able to:
• Give overview of sodium chloride equivalent method
• Determine the isotonicity by sodium chloride equivalent method

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Sodium Chloride Equivalent Method

• The Sodium Chloride equivalent method (E) is the amount of sodium which has the same osmotic effect (based on number of particles) as 1g of the drug sample calculation
• Percentage of sodium chloride for adjustment to isotonicity = 0.9 - ( % of medicament in solution x sodium chloride equivalent of medicament)
• When adjustment is to be made with a substance other than sodium chloride first calculate the required percentage of sodium chloride and then divide this by the sodium chloride equivalent of the chosen adjusting substance

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EXAMPLES

Procedures to be followed

Assignment

1. Calculate the percentage of anhydrous dextrose required to render a 1% solution of ephedrine hydrochloride iso – osmotic with body fluid

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2. Calculate the amount of NaCl required to make the following ophthalmic solution isotonic.

3. Calculate the percentage of sodium chloride needed to make an injection containing morphine sulphate 1%, hyoscine hydrobromide 0.04% and sodium metabisulphate 0.1% iso – osmotic with blood plasma

E values are 0.14, 0.12 and 0.70 respectively

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Key Points

• The Sodium Chloride equivalent method (E) is the amount of sodium which has the same osmotic effect (based on number of particles) as 1g of the drug sample calculation 
• Percentage of sodium chloride for adjustment to isotonicity = 0.9 - ( % of medicament in solution x sodium chloride equivalent of medicament) 
• When adjustment is to be made with a substance other than sodium chloride first calculate the required percentage of sodium chloride and then divide this by the sodium chloride equivalent of the chosen adjusting substance

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Determination of Isotonicity by Molecular Concentration Method

Learning Tasks

• By the end of this session students are expected to be able to:
• Explain isotonicity by molecular concentration method
• Determine the isotonicity by molecular method

• Before we proceed with Determination of Isotonicity by Molecular Concentration Method it is preminary we first discuss the concept related to calculation of dissociation ( i) factor

Other formula for calculating ( i )

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• i = ( % X P ) + ( 100% -%)
• Where
• P : is the number of ions after dissociation
• % : dissociated percentage
• (100-%) : undissociated percentage

NaCl equivalent method (continuation of NaCl equivalent method under session 13)

• NaCl equivalent “E”

Amount of NaCl that is equivalent to(i.e., has the same osmotic effect (same f.p.d) as ) 1 gm of drug

• 1^st calculate E _NaCl
• 2^nd add NaCl to reach 0.9%

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​

​

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How to calculate E_NaCl ?

=

L = Molar freezing point (constant)

How to calculate amount of NaCl

Example I

• Calculate E_NaCl of drug (M.wt=187, L_iso=3.4)?

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​

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• How much NaCl needed to make 2% of this drug isotonic?

Example II

• Calculate amount of NaCl needed to adjust 1.5% Atropine SO₄ (E_NaCl =0.12gm)
• =0.9 –(W x E)

= 0.9 –(1.5x 0.12)

= 0.72 gm of NaCl should be added

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Molecular Concentration Method

• Molecular concentration: number of units i.e. molecules or ions or both present in a solution.
• A solution containing 1 g molecule of a non- ionizing solute in 22.4 liters at normal temperature and pressure (NTP) has an atmospheric pressure of one atmosphere.
• Therefore a solution containing one gram molecule in 1 litre (a mole solution) will have osmotic pressure of 22.4 atmosphere.

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• The molarity or molar concentration of a solute is defined as the number of moles of solute per liter of solution (not per liter of solvent!): 

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• M=N/L Where M=molarity, N = number of mole and L = 1 litre of a solution
• N =M/MW where M = mass or weight and MW = molecular weight of compound

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Determining the Isotonicity by Molecular Concentration Method

• Calculate MW of compound x which contains 9.06g isotonic solution given dissociation factor is 1.8.

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• From freezing point = 1.86Ni
• Where N = Number of mole and i dissociation factor
• N = m/ mw and i = (% x p) + (100% - %) where p = number of ions after dissociation
• Now
• 0.52 = 1.86 x N x 1.8
• N = 0.52/ 1.86 x 1.8
• N = 0.1553166
• But N = M/MW
• MW = m/N therefore 9.06g/0.1553166
• Mw =58.33

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3-White – Vincent method

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• Principle:
• 1^st Addition of H2O to drug to make it isotonic
• 2^nd addition of isotonic vehicle to bring solution to final volume

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How to calculate amount of H₂O ?

• Suppose preparing 30ml of 1% drug isotonic with body fluid(E_NaCl =0.16gm)
• 1gm 100ml

? 30ml =0.3gm

• Amount of NaCl eq. to 0.3 drug

= 0.3 x 0.16 =0.048gm

• 0.9 gm 100 ml
• 0.048 gm ? ml

=5.3 ml

II example

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Add volume of H₂O and then complete with isotonic solution

Phenacaine HCl 0.06 gm (E_NaCl=0.16)

Boric acid 0.3 gm (E_NaCl=0.5)

sterile distilled H₂O up to 100 ml

V = 111.1 x(weight x E_NaCl)

V =111.1 x [(0.06x0.16)+(0.3x0.5)] = 17.7 ml H₂O

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​

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Key Point

• Molecular concentration is the number of units i.e. molecules or ions or both present in a solution.  
• A solution containing 1 g molecule of a non- ionizing solute in 22.4 liters at normal temperature and pressure (NTP) has an atmospheric pressure of one atmosphere.
• Therefore a solution containing one gram molecule in 1 litre (a mole solution) will have osmotic pressure of 22.4 atmosphere

Assignment

• Compound x contains 9.07g dissociate by 80% into two ions. Calculate molecular weight of isotonic solution

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Calculations Involving Milliequivalent

Learning Tasks

• By the end of this session students are expected to be able to:
• Explain Milliequivalent
• Calculate Milliequivalent

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Introduction to Milliequivalent

• Express the concentration of electrolytes in solution.
• This unit of measure is related to the total number of ionic charges in solution, and it takes note of the valence of the ions. In other words, it is a unit of measurement of the amount of chemical activity of an electrolyte.

• The equivalent weight of an element is the gram atomic weight divided by its valency.

OR

• A Milliequivalent of an ion is the ionic weight in mg divided by the valence of that ion
• Divide the Equivalent by 1000, and you get answer in gram when necessary
• For example, Na has an atomic weight of 23. So 23 mg of Na+ in solution means 1 mmol of Na⁺ is in solution. We could also say 1 mEq of Na⁺ is in solution.
• Ca has an atomic weight of 40. So 40 mg of Ca²⁺ in solution means 1 mmol of Ca²⁺ is in solution. In this case, 2 mEq of Ca is in solution.

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• The number of mEq of each ion obtained from a salt in solution therefore depends on the valency of the ion e. g. Sodium chloride has 1 Na⁺ and Cl^- in each molecule and both have the valency of one

​

• In this case mmol and mEq give numerically the same results, because both ions have the valency of one

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N.B: The molecular weight of H2O is 18

Example 2

2. solution contains 90 mEq Na⁺, 60mEq K⁺ and 150 mEq Cl^- per litre. Convert to g/L

• A convenient way to solve the question is first to arrange the mEq in a table, so that the composition of the salt is obvious

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• NaCl: As 1 mEq Na+ or Cl^- is provided by 58.5mg NaCl, then 90mEq will be provided by

58.5 x 90

58.5x 90 = 5265mg

KCL: The amount is found respectively

74.5 x 60 = 4470mg

Therefore the solution contains 5.265g NaCl and 4.47g KCL per litre

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Key Points

• A Milliequivalent of an ion is the ionic weight in mg divided by the valence of that ion
• The number of mEq of anions cations in any amount of salt is always the same, whereas the number of mmol of anions and cations differs with certain salts, depending on the number of ions in the molecules

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Assignment

Assignment cont…

• How many calcium chloride are needed to provide 1 mmol of Ca2+ and 1 mmol of Cl-
• How many mmol of Cl- are obtained from 234 mg sodium chloride?

Convert the following formula to g/L

Na⁺ ………………………..30 mmol

K⁺ ………………………….10 mmol

Mg²⁺ ……………………......4 mmol

Cl^-………...……………… ..18 mmol

HPO₄²⁺ …………………….15 mmol

Water for injection …….. To 1000 mL

The salts used are Na₂HPO₄.12H₂O, KCl and MgCl₂. 6h2O

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Convert the following formula to mEq/L

Na⁺ ………………………..40 mmol

K⁺ ………………………….10 mmol

Mg²⁺ ……………………......5 mmol

Cl^-………...……………… ..40 mmol

HPO₄²⁺ …………………….10 mmol

Water for injection …….. To 1000 mL

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Calculations Involving Millimoles

Learning Tasks

• By the end of this session students are expected to be able to:
• Give overview of calculations involving Millimoles
• Perform calculations involving Millimoles

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Introduction to Millimoles

• A Millimole (mmol) of an element, a compound, or an ion is its atomic, molecular, or ionic weight respectively e.g. the ionic weight of Ca²⁺ is 40, therefore, 1 mmol Ca²⁺ = 40mg calcium
• The number of mmol of each ion obtained from a salt in solution depends on the number of each ion in the molecule of the salt. e.g. Sodium chloride (NaCl, mol wt.: 58.5) has 1 Na and 1 Cl in each molecule. Hence 1 mmol NaCl ( 58.5mg) provides 1 mmol Na (23mg) and 1 mmol Cl (35.5mg)

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• Calcium chloride (CaCl₂.2H2O, mol wt.: 147) has 1 Ca²⁺ and 2Cl in each molecule. Hence 1mmolCaCl2.2H2O (147mg) provides 1 mmol Ca²⁺ ( 40mg) and 2mmol Cl(71mg)
• Therefore the amount of mg salt containing 1 mmol of a specified ion is calculated by the following equation:
• mg salt containing 1 mmol of specified ion

= molecular weight of the salt number of specified ions in the molecule

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Example:

Quiz

• 367mg calcium chloride provide how many mmol Ca²⁺ and how many mmol Cl^-?

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Key Points

• A Millimole (mmol) of an element, a compound, or an ion is its atomic, molecular, or ionic weight respectively e.g. the ionic weight of Ca²⁺ is 40, therefore, 1 mmol Ca²⁺ = 40mg calcium
• The number of mmol of each ion obtained from a salt in solution depends on the number of each ion in the molecule of the salt. e.g. Sodium chloride (NaCl, mol wt.: 58.5) has 1 Na and 1 Cl in each molecule. Hence 1 mmol NaCl ( 58.5mg) provides 1 mmol Na (23mg) and 1 mmol Cl (35.5mg)

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Calculations Involving Milliosmoles (mOsmol)

Learning Tasks

• By the end of this session students are expected to be able to:
• Give introduction to calculations involving milliosmoles
• Perform calculations Involving Milliosmoles

Introduction to Milliosmoles

• Electrolytes regulate body water volumes by establishing osmotic pressure which is proportional to the total number of particles in solution.
• The osmotic pressure of a solution is expressed in milliosmoles (mOsm)

• The term Osmolarity is used to express the strength in Osmol per liter and indicates the total ionic concentration of the solution
• Osmolar concentrations reflects the number of particles ( molecules as well as ions) of total solutes per volume of solution which in turn determines the osmotic pressure of the solution.

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• Labels of some pharmacopoeia solutions that provide intravenous replenishment of fluids, nutrients, electrolytes and the osmotic diuretic mannitol are required to state osmolar concentration.

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• This information indicates to the practitioner whether the solution is hypotonic, isotonic or hypertonic with regard to biologic fluids and membranes

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Since the unit that is used to measure osmotic concentration is Milliosmoles then;

• For non – electrolytes e.g. dextrose 1 mmol (formulary weight in mg) represents 1 mOsmol

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• For electrolytes, the total number of particles in solution depends on the degree of dissociation of the substance in question, assuming complete dissociation

​

• 1 mmol of NaCl represents 2 mOsmol ( Na⁺ and Cl^-) of the total particles

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• 1 mmol of CaCl₂ represents 3 mOsmol ( Ca2⁺ and 2Cl^-) of the total particles

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• 1 mmol of Sodium citrate (Na₃C₆H₅O₇) represents 4 mOsmol ( 3Na⁺ -C₆H₅O₇) of the total particles

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• The milliosmolar value of separate ion of an electrolyte may be obtained by dividing the concentration in mg per liter of an ion by its atomic weight

​

• The milliosmolar value of the whole electrolyte in solution is equal to the sum of the milliosmolar value of separate ions

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• According to USP, the ideal osmolar concentration may be calculated using the following equation:

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Examples

• A solution contains 5% anhydrous dextrose in water for injection. How many mOsmol per liter are represented by this concentration?
• Formula weight of anhydrous dextrose = 180

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• 1mmol of anhydrous dextrose (= 180 mg) = 1 mosmol
• 5% solution contains 50g or 50,000mg/L
• Therefore:

mOsmol/L = 50,000 = 278mOsmol/

180

OR Using USP equation:

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• mOsmol/L = 50 x 1000 = 278 mOsmol/ L

180

More Examples

• How many mOsmol are represented in a liter of a 0.9% sodium chloride solution

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Key Points

• Milliosmoles (mOsmol) is an expression of the osmotic activity of 1 Millimole
• The osmotic activity of a solution may be stated in terms of Milliosmoles which is an expression of the osmotic activity of 1 Millimole
• The term Osmolarity is used to express the strength in mOsmol per liter and indicates the total ionic concentration of the solution
• This information indicates to the practitioner whether the solution is hypotonic, isotonic or hypertonic with regard to biologic fluids and membranes

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Calculations Involving Osmolarity

Learning Tasks

• By the end of this session students are expected to be able to:
• Give introduction to calculation involving Osmolarity
• Concept on osmolarity vs osmolality
• Perform calculations Involving Osmolarity

Osmolarity

• Osmolarity is defined as the number of osmoles of solute per liter (L) of solution. It is expressed in terms of osmol/L or Osm/L. Osmolarity depends on the number of particles in a chemical solution, but not on the identity of those molecules or ions.

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Sample Osmolarity Calculations

• A 1 mol/L NaCl solution has an osmolarity of 2 osmol/L. A mole of NaCl dissociates fully in water to yield two moles of particles: Na⁺ ions and Cl^- ions. Each mole of NaCl becomes two osmoles in solution.
• A 1 M solution of sodium sulfate, Na₂SO₄, dissociates into 2 sodium ions and 1 sulfate anion, so each mole of sodium sulfate becomes 3 osmoles in solution (3 Osm).
• To find the osmolarity of a 3% NaCl solution, you first calculate the molarity of the salt solution and then convert the molarity to osmolarity.

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• Convert percent to molarity:� 3 % = 3 grams

100 ml = 3 grams / 0.1 L = 30 g/L molarity NaCl = moles / liter = (30 g/L) x (1 mol / molecular weight of NaCl)

• Look up the atomic weights of Na and Cl on the periodic table and add the together to get the molecular weight. Na is 22.99 g and Cl is 35.45 g, so the molecular weight of NaCl is 22.99 + 35.45, which is 58.44 grams per mole.
• Plugging this in:
• molarity of the 3% salt solution = (30 g/L) / (58.44 g/mol)�molarity = 0.51 M
• You know there are 2 osmoles of NaCl per mole, so:
• osmolarity of 3% NaCl = molarity x 2�osmolarity = 0.51 x 2�osmolarity = 1.03 Osm

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Calculations Involving Constituted Solutions

Learning Tasks

• By the end of this session students are expected to be able to:
• Give overview of calculations involving constituted solutions
• Perform calculations involving constituted solutions

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Introduction to Calculations Involving Constituted Solutions

• Process of mixing and diluting solutions
• Parts of Solutions

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Terms

• Solute
• Substance to be dissolved or diluted
• Can be either solid or liquid
• Solvent
• Substance (liquid) that dissolves another substance to prepare solution
• Often referred to as diluent
• Solution
• Resulting mixture of solute plus solvent

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Terms cont…

• Caution
• Before reconstituting injectable drugs, read and follow label or package insert directions carefully
• Check drug
• Check diluent dates

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When reconstituting injectable medications, one must determine both type and amount of diluent to be used

• Sterile water and 0.9 percent NaCl commonly used
• Some drugs are supplied with special diluent
• Determine volume in mL of diluent to be used
• Check that route noted on drug label matches route ordered
• Reconstitute drug and note resulting supply dosage on vial
• Note if single-dose or multiple-dose vial

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Example Drug Label

Performing Calculations Involving Constituted Solutions

Reconstituting Parenteral Solutions: Single Strength

Order: Zithromax 400 mg IV daily for 2 days

Available: Zithromax 500 mg vial for IV infusion

Drug is in powder form with directions on label that state, “Constitute to 100 mg/mL with 4.8 mL of Sterile Water for Injection

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Procedure:

1. How much and what type of diluent is needed?

4.8 mL of sterile water

2. What is the dosage concentration after reconstitution?

100 mg per mL

3. What is the total volume after reconstitution?

5 mL

4. Given the ordered dose, how many doses are available in the vial?

One

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• To reconstitute Zithromax:

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• Choose 5 mL syringe
• Withdraw 4.8 mL of sterile water
• Add 4.8 mL of sterile water to Zithromax powder and shake well

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Determine amount needed for dose ordered

1. Convert

• No conversion needed

2. Think

• Need 400 mg
• Have 100 mg per mL
• Need four times that amount

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Reconstituting Parenteral Solutions: Multiple Strength

• Some parenteral powdered medications have directions for preparing several different solution strengths
• Penicillin G potassium 1,000,000 units vial
• Reconstitution instructions note four different solution concentrations as determined by amount of diluent added

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• Order: Penicillin G potassium 300,000 units IM every 6 h for adult patient
• Available: Penicillin G potassium 1,000,000 unit vial
• Given the reconstitution concentrations on the previous slide, which should you use when preparing to administer the ordered dose?

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Consider:

• Dose ordered
• Patient receiving dose
• Consider:
• Volume and concentration that results with each noted diluent volume
• Smaller the amount of diluent added, stronger the resulting solution concentration
• Consider maximum recommended volumes for injection by patient and parenteral route

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• Considering previously mentioned factors, adding 4 mL of diluent results in reasonable volume and medication concentration
• Results in concentration of 250,000 units per mL
• How many mL are needed to deliver ordered dose of 300,000 units?

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Rules When reconstituting multiple-dose injectable medications:

• Label reconstituted drug noting resulting supply dosage
• In previous example, 250,000 units per mL
• Verify length of drug potency and storage directions
• Label on penicillin G potassium notes that solution “may be kept in refrigerator for one (1) week”

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Complete label of reconstituted multiple-dose vial, noting:

• Date and time of preparation
• Supply dosage
• Length of potency
• Expiration date
• Storage directions
• Own initials

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