Dosage Form Design PDF
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University of KwaZulu-Natal
Prof Thiru Govender
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These notes cover dosage form design, discussing various routes of drug administration including oral, rectal, parenteral, topical, and respiratory. The document details biopharmaceutical considerations, drug properties, and therapeutic factors. The specific properties of dosage forms are also discussed, such as solubility, stability, particle size, and more.
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Dosage Form Design Prof Thiru Govender Discipline of Pharmaceutical Sciences The Design Of Dosage Forms Principal objective: To achieve a predictable therapeutic response for a drug included in a formulation which is capable of large scale manufacture w...
Dosage Form Design Prof Thiru Govender Discipline of Pharmaceutical Sciences The Design Of Dosage Forms Principal objective: To achieve a predictable therapeutic response for a drug included in a formulation which is capable of large scale manufacture with reproducible product quality. Different dosage forms can be designed for administration by all possible delivery routes to maximize therapeutic response. Example of Administrative Route Dosage Form Oral Tablets Rectal Suppositories Topical Ointments Parenteral Injections Lungs Aerosols Nasal Inhalations Eye/Ear Solutions/suspensions Before a drug substance can be successfully formulated into a dosage form, many factors must be considered: 1. Biopharmaceutical considerations → factors affecting absorption of the drug from different administration routes. 2. Drug factors → physical and chemical properties of drugs. 3. Therapeutic considerations → consider the disease to be treated and patient factors e.g. Age, sex etc. Pathways a drug may take following administration of a dosage form by different routes Biopharmaceutics → study of the relationship between the physical, chemical and biological sciences applied to drug, dosage forms and drug action. Drug must be in solution to be absorbed by absorbing membranes of the skin, g.i.t and lungs into body fluids. Membrane penetration of drugs occurs via 1. Passive diffusion and 2. Specialized transport mechanisms where: a) Process is driven by concentration gradient. b) An energy source may be required Routes of Drug Administration 1. Oral Route 2. Rectal Route 3. Parenteral Route 4. Topical Route 5. Respiratory Route 1. Oral Route (p.o) per OS Most frequently used. Indicated for systemic effect via absorption through GIT. Some Drugs → intended to dissolve in mouth → leads to rapid absorption. Simplest, most convenient and safest means of drug administration Disadvantages: Slow onset of action. Irregular absorption. Destruction of certain drugs by enzymes and secretions of GIT e.g. insulin Gastric emptying time – important for effective drug absorption from intestine – if it is too slow can degrade certain drugs. pH of stomach and large intestine approx. 1 and 7 respectively – differences will dictate ionization and lipid solubility and therefore drug absorption. Membranes are more permeable to unionized rather than ionized forms. Oral dosage forms → tablets, capsules, suspensions, solutions and emulsions, powders, effervescent powders. 2. Rectal Route Used more frequently for local effect rather than systemic effect. Suppositories which are introduced into body cavities e.g rectum, vagina etc → melt → leads to release of drug. Suppository base or drug carrier is important, e.g. cocoa butter. Rectal route is indicated for drugs inactivated by oral route or: If patient is vomiting If patient is unconscious Drugs administered rectally may also enter the systemic circulation without passing through the liver → therefore advantageous for drugs inactivated by liver after oral administration. Also have Vaginal and Urethral administration Disadvantage: Inconvenient Irregular drug absorption Administered as solution, suppository or emulsion form 3. Parenteral Route Drug is injected via a needle into the body at different sites and depths. 3 main parenteral routes: subcutaneous (s.c.), intramuscular (i.m.) and intravenous (i.v.) Rapid absorption occurs. Used for: Emergency situations Patient is unconscious/ unable to accept by mouth. In cases where drugs are destroyed, inactivated or poorly absorbed after oral administration. Provides more predictable blood levels than oral. Administered as sterile solutions/suspensions of drug in water/acceptable vehicle-rapid absorption. Suspensions → have slow absorption because drug is not in solution. When Drug is in oily vehicle in the aqueous surrounding of body fluids-also slows absorption and is slow acting. Can be formulated to provide a depot effect → provides a reservoir of drug which is slowly released into systemic circulation → applies to IM injections. SC injections → are aqueous solutions or suspensions → are administered in vicinity of blood capillaries → drug diffuses into capillary. IV injections → sterile aqueous solutions injected directly into vein. Volume delivered range: mL to litres 4. Topical Route Drug Applied to skin → for local effect (e.g. wounds). Can be used for systemic effect (e,g patches for pain) → however percutaneous absorption is poor and erratic. Drug absorption is via the sweat glands, hair follicles, sebaceous glands and through the stratum corneum Drugs used for local effect→ include antiseptics, antifungals, anti-inflammatories, emollients Pharmaceutical topical formulations →include drug in a semi solid base eg. ointments, creams, ZnO pastes, gels, lotions, solutions. Base for ointment/cream/lotion is important → because it determines drug release. Also Includes eye, ear, nose preparations → as they are topical surfaces for drug administration. 5. Respiratory Route Lungs → provide excellent surface for absorption of drugs delivered in gaseous or aerosol mist form. Particle size determines extent to which they penetrate alveolar region-zone for rapid absorption. Useful for treatment of asthma → powder aerosols or metered aerosols. Now being used for administering peptides and Proteins which cant be taken orally. For stable and efficacious product → important to study physical and chemical properties of drug substance. Organoleptic Properties Dosage form → must be acceptable to patient. Drugs can be unpalatable and unattractive in natural state. Flavour and perfumes → are required for liquid oral dosage forms. In solids if there is a bitter taste: Consider capsule vs tablet. Citrus flavouring - common. Solubility and stability of flavour is important. Colours – improve natural colour, mask colour change, complement flavour or perfume, have psychological impact, improve safety. Particle Size & Surface Area ↓particle size of drug → leads to ↑ surface area i.e. surface area per unit weight. Poorly soluble drugs – are more readily available if formulated in finely subdivided particle size e.g. indomethacin. Drug dissolution rate can be affected by particle size of excipients even if drug in appropriate size e.g. tablet → lubricating powders can provide hydrophobicity to a formulation which inhibits drug dissolution. Micronization (size reduction) → can cause polymorphic and surface energy changes → can ↓ chemical stability Drug particle size → affects uniformity of dosage form- leading to variable results. Solubility Drug must exhibit at least limited aqueous solubility for therapeutic efficacy. If very insoluble → leads to erratic, incomplete absorption → therefore use more soluble salt or ester form of drug. Note that salts in solution → can precipitate in GIT – can affect bioavailability. Micronising/complexation can be employed. pH dependent solubility properties of acidic or basic drug can also influence activity. Dissolution For drug to be absorbed → it must be dissolved in the fluid at the site of absorption Dissolution of drug described by Noyes- Whitney Equation dm/dt = KA(Cs – C) K = Dissolution Rate Constant A = Surface Area of Solids Cs = Concentration of Drug in Saturated Layer C = Concentration of Drug in Dissolution Medium of Time t. Partition Coefficient & pKa Relatively insoluble compounds-dissolution is often rate determining step for absorption. The rate of permeation across biological membranes may be the rate determining step for some soluble compounds. Permeation rate can be altered through molecular modifications of drug. Absorbing membrane acts as a lipophilic cell membrane barrier to the passage of drugs → which is related to the lipophilic nature of drug molecules. Partition coefficient (o/w) is a measure of the lipophilic character of drugs. Majority of drugs are weak acids or bases. Drug exists in ionized or unionized form → depends on the pH and whether drug is a weak acid or weak base. Absorbing membrane → is more permeable to unionized form of drug than to the ionized forms because of greater lipid solubility of unionized species and to the highly charged nature of the cell membranes which leads to binding or repelling of the ionized drug thereby↓ penetration. Main factors affecting absorption are therefor pH at the site of absorption and lipid solubility of the unionized species. Crystal Properties, Polymorphism Drug substance can be: Amorphous (without regular molecular lattice arrangement) Crystalline Anhydrous Hydrated (various degree of hydration) Also may exist in more than one crystalline form with different lattice arrangements → polymorphism. Only one form is stable at a particular temperature and pressure → other forms are metastable → convert at different rates to stable crystalline form. Physical properties can vary : solubility, dissolution, stability, flow. Stability Refers to chemical stability and compatibility with formulation excipients-affects shelf life/safety. Packaging of dosage formà important contributing factor to stability. Drugs undergo Decomposition/ degradation – may be due to heat, O2, light, moisture. Therefore formulation may have low moisture content specifications. Other precautions will include the following: Moisture resistant packaging for drugs sensitive to hydrolysis e.g. blisters Anti-oxidants can be included for Oxygen sensitive drugs Amber-coloured bottles for light sensitive drugs. Buffers can be used - to control pH of preparation Preservatives used to control bacterial growth. Other Properties must also be suitable for manufacturing procedure and large scale manufacture e.g. Flowability Hygroscopicity Compressibility The following factors will also affect the type of drug and dosage form required: Nature of illness Systemic vs local effect Duration of action Emergency situation Specific targeting of disease site will require specialised dosage forms such as liposomes, nanoparticles etc) Patient related factors ○ Age, weight ○ Physiological and metabolic factors Dose
