Pharmaceutical Product Stability PDF

Stability Stability - relates to various chemical, physical and microbiological reactions that may change original properties of the preparation during storage, transport and use. - Expressed as ‘shelf life’: which is the time during which the product is fit for intended use under...

Stability Stability - relates to various chemical, physical and microbiological reactions that may change original properties of the preparation during storage, transport and use. - Expressed as ‘shelf life’: which is the time during which the product is fit for intended use under specific conditions of storage. - Generally, it is the time from manufacture of the product till the potency of the active substance has been reduced 10% under specific storage conditions. - Loss of potency; less therapeutic eFicacy. - Degradation to toxic products. - Formulation becomes unsuitable for application. - Unacceptable appearance (colour change, bad smell, microbiological growth etc). - Requirement for approval by regulatory agencies. Stability types - Physical, chemical, and photochemical, microbiological. - One type can lead to another. Physical instability - Changes in solubility - Emulsion cracking - Changes in tablet dissolution or disintegration. - Changes in semisolid rheology. - Caking of suspensions. - Packaging failure (can also lead to chemical or microbiological instabilities). - Biologics à aggregation, denaturation. Solid state reactions occur in solution. - Major source of the solvent o Residual moisture or solvent from wet granulation. o Moisture absorbed (in)onto excipients, such as starch and lactose. o Moisture in the capsule shell may migrate, through direct contact or vapour phase. o A melt of the drug itself or an ingredient in the formulation that has a low melting point. o A solvate or hydrate that loses its lattice solvent with time and temperature fluctuation. o High moisture à higher risk of reaction. Method of stabilisation - Altering the properties of solid drugs. o Increasing melting point. à by swapping some additives that have higher melting temperature. o Choosing a non-hygroscopic form (crystal or salt form) o Reducing solubility by choosing a less soluble salt. o Micellar inclusion. o Complexation. o Engineering of the particles (shape) - Physically separating the reacting species. o Minimising the contact among the interacting drugs and excipients, and water. o Techniques: § Coating with polymers/microencapsulation. § Multi-layer tablet. § Tablet in a tablet. § Tablet in a capsule. Main physical degradation routes - 1) Polymorphic transition (α, β, γ, forms), e.g., graphite to diamond. o “…polymorphic forms show significantly diFerent solid-state properties such as dissolution rate, mechanical properties, crystal habit, melting point, and pKa.” o Examples of polymorphism of pharmaceutically important compounds. § Aspirin § Acetaminophen § Atorvastatin § Ritonavir § Axitinib - 2) Crystallisation of amorphous material. o Poorly soluble drugs dissolve more readily when in an amorphous state. o Tend to convert to a more thermodynamically stable state. o then have altered release kinetics. o can convert during long term storage. - 3) Hydrate/solvate formation / seeding eJect. o E.g. carbamazepine. o Readily convert to dehydrate in water (in minutes). o Very slow hydration with atmospheric water vapor (take 5 weeks to see any conversion at 97% RH) o After wet granulation and drying (maybe insuFicient drying) traces of the dihydrate are retained, act as seed material, and rehydration takes place faster and would also happen at lower humidity values. à takes 25 days for complete hydration at 93%RH. - 4) Vaporisation  o E.g. nitro-glycerine - 5) Sorption o E.g. Enalapril o Incompatible with microcrystalline cellulose. o Cause dissociation of the amine maleate. o The free amine is unstable. o Compatible with Ca Phosphate – No such preferential adsorption occurred. o Molecules of a drug or excipient may be adsorbed from solution in water or other solvent on to the surface of solid particles. o à Adsorption occurs in suspensions not in solutions. It is solid-state property). - 6) Particle sedimentation o For suspensions, emulsions, creams, and ointments. Package failure. - Release of container components into formulation increased by: o Temperature o Agitation o Character of plastic/rubber additives - Transport of gasses o Oxygen o Carbon dioxide o Water vapour - Examples: o Adsorption of preservatives onto/ the contained inner wall (loss of preservation activity). Chemical and Photochemical Instability - How to distinguish between chemical and photochemical instability? o Making or breaking chemical bonds à chemical instability. Types of chemical degradation - Hydrolysis / fragmentation (biologics) - Oxidation - Deamidation - Isomerisation - Epimerisation - Reduction (less common, e.g., Ketoprofen =O -OH) - Polymerisation. (formation of dimers, e.g., Captopril and Amoxycillin) Hydrolysis - If the drug id a derivative of carboxylic acid or contains functional groups based on this moiety (ester, amide, lactone, lactam, imide, or carbamate) then the drug us susceptible ti hydrolytic degradation. Conditions causing breakdown. - Presence of hydroxide ion (higher pH) - Presence of hydrogen ion (lower pH) - Presence of divalent metal ions - Heat - Light - Solution polarity and ionic strength - Higher drug concentrations Hydrolysis Oxidation - Next most common pathway for drug breakdown. - Eliminated by the storage under anaerobic conditions. - Auto-oxidation - Or - Initiation à propagation à termination o E.g. Steroids and sterols (carbon=carbon, alkene -> peroxyl radical) o Polyunsaturated fatty acids (vegetable oil) o Polyene antibiotics (amphotericin B) - Stabilisation against oxidation o Nitrogen, o Carbon dioxide o Heavy metal (iron, cobalt, nickel) o Temperature o Inhibitors: HOMEWORK Oxidation - Susceptible groups o Phenols (Steroids) o Catechols (Catecholamine) o Thiols (Captopril) o Amines (?) o Aldehydes (?) Autooxidation - Autocatalytic reaction (slow start then rapid acceleration) - Radical generation is thermal, photochemical or metal-ion initiated. - When a small amount of oxidation occurs, the peroxy radicals will lead to faster deterioration as they reinitiate the oxidation process. - How to avoid? o Protect from light, oxygen, and temperature. o Add peroxide decomposing substance (sulfur) o Add antioxidant (e.g. ascorbic acid, ascorbityl palmitate). o Add metal chelating agents (e.g. EDTA). Oxidation of benzaldehyde Photochemical degradation - Degradation when expose to light – as a result loss of potency. - Photodegradation – storage and use. - Photosensitisation: Some drugs are able to transfer the energy to other molecules which will in turn react. - Kinetics depends on the drug concentration. Photostability testing - Expose the drug (pre-formulation) to sunlight simulating light source (SSLS). - Exposes the finished product (tablet, capsules) in its final container and market pack to SSLS. - Stabilisation: o Glass containers (colour) o Coatings Isomerisation - Conversion of a substance to its geometric isomer (Spatial re-orientation around double bonds). o E.g. Trans vitamin A to inactive cis Vitamin A - or optical isomer, Racemisation (D-L or L-D) o e.g., L-hyoscyamine (3x) activity of the racemic form (DL)-Atropine. - Epimerisation – toxic Shelf life - Time by which 10% of the active substance is degraded. - T90% - Determined according to the order of the reaction kinetics. - Zero, 1st order and 2nd order degradation kinetics. - Accelerated stability testing and Arrhenius equation. Zero order Zero order – half-life Shelf-life First order Half life Shelf-life 2nd order Half-life Shelf life Accelerated stability testing. - Arrhenius equation. Accelerated stability testing. - Conduct the experiment at elevated temp for few hours, days or months… - Get the ks - - Higher the temperature, faster the reaction. - - Temperature dependence of rate constant & Ea. Properties to be measured to indicate instability. - Drug content. - Level of degradation products. - Colour change. - Viscosity change - Melting point change Methods used for detection of in-vitro interactions. - Thin layer chromatography - UV-spectroscopy. - High pressure liquid chromatography (HPLC) - DiFerential thermal analysis (DTA) - DiFerential scanning calorimetry (DSC) - Other types of chromatography - Fluorescence spectroscopy - Light scattering - Osmometry - NMR & MS - Turbidimetry - Microscopy (TEM, optical etc.) How to avoid or minimise the in-vitro interactions? - Select the proper excipients. - Carry out pre-formulation tests. - Adjust the conditions to avoid or minimise interactions. (e.g. adjust pH) In solid dosage forms the in-vitro interactions could be avoided by number of techniques including: - Separate granules - Multiple tablets - Microencapsulation technique. Avoiding moisture - Packaging o Ampoules Vs Vials o Glass Vs Plastic - Use desiccant to absorb moisture. - Minimise exposure. o Control Humidity during manufacture. o Replace air with Nitrogen in headspace. As a pharmacist… - Check storage conditions in pharmacy. - Check expiry dates. - Rotation of Stock. - Changes in appearance of Stock. - Damaged packaging. - Advice on webster packs (nursing homes). - Counselling patients o Compliance o Storage conditions o Expiry dates o Special conditions (extemporaneous, eye drops, Glyceryl trinitrate tablets) As a hospital pharmacist… - Advice to nursing staF on product’s storage conditions. - Advice on TPN storage and discarding date. - Advice on chemotherapy…etc. Conclusions - Developing a stable formulation requires: o Through investigation of the intrinsic stability of the compound in preformulating stage of development. o Thermal and photo. o Against oxidation. o Relevant excipient compatibility studies. o Identify low risk excipients. o Detailed stability studies of the formulations. o Accelerated conditions. o Understand the stability in formulations. TGA process TGA guidelines - Purpose: To ensure product meets physical, chemical and microbial specifications throughout its shelf-life under the specified conditions. - Required in dossier. o Study design. o Test methods. o Commentary on results. o Conclusions and summary of claims.