Formulation Flashcards

Question

Disintegration parameters

Answer 1

Crude measure of 'availability' of drug * Raise and lower in water at 37° * Normally 15 minutes for uncoated tablets

Answer 2

May give better link to bioavailability * Controls batch variability? * Required in all USP monographs * Limited in Ph. Eur. * Enteric coated tablets * But expected in registration dossiers Amount dissolved (Q) in time (T) using specified apparatus and conditions  Calibration and control important * Physical parameters * Temperature and composition of media * Degassing! * Speed, position, wobble etc. of basket or paddle * Performance verification * Mechanical tests * USP calibrator tablets * Prednisone, Salicylic Acid Test carried out on at least 6 tablets * USP → multi stage acceptable criteria up to 24 tablets * Ph. Eur. → Q = 75%, T = 45 min. Retest possible if 1 tablet fails * For enteric coated tablets → 2 stage test * Acid resistance (0.1M HCL) * Higher pH buffer

Answer 3

Balance required to give robustness and disintegration  Electromechanical test equipment  Calibrate directly or by 'mechanical tablets' Multiple designs of tester * Schleuniger * Erweka * CI  Non destructive by NIR  Combination instrument * Hardness * Thickness * Diameter Breaking strength or hardness refers to the force necessary to cause failure of the tablet under load

Answer 4

Important in packaging * But beware if you register a specification!

Answer 5

This is a measure of resistance to abrasion * Measure of robustness during coating, packaging and use * Performed on uncoated tablets For uncoated tablets * 10 – 20 tablets * 25±1 rpm for 4 minutes * NGT 1% mass loss Measures resistance to abrasion. Perhaps the most important parameter to consider for forward processing. Tablets with friabilities approaching 0.5% will be very difficult to coat.

Answer 6

Solution * Single phase liquid system * Solvent and solute(s)  Suspension * Liquid continuous phase, second suspended solid phase  Emulsion * Liquid continuous phase, second emulsified liquid phase Solution Solvent * Aqueous/Non aqueous  Solute * Solubility enhancement  Excipients * Taste masking Solvent Aqueous (water) * Most common * Correct quality grade employed * Purified water * Chemical and microbiological quality  Non-aqueous * Alcohol, glycols, * Unusual * Quality important e.g. potable alcohol (ethanol) Solute Anything dissolved in solvent  Solubility enhancement * pH adjustment * Co-solvent * Surfactant solubilisation * Complexation  Other excipients * Buffers * Tonicity * Viscosity Sweeteners Sucrose * Oldest, best, simplest * Additional benefits * Antimicrobial * Disadvantages * Calorific (diabetics), cariogenic  Other Sugars * Lower sweetening potential  Artificial Agents * Saccharin, aspartame, acesulfame, cyclamate * Low concentrations required * Distinctive taste – mask low sucrose concentrations Flavours Enhance taste masking effect of sweetening agents  Smell and taste e.g. peppermint  Concentrated alcoholic solutions requiring dilution for manufacturing  Natural or synthetic * Synthetic * Cheaper, consistent, stable * Natural * Microbiological quality  Traditional tastes * Antacids – minty Colour Final portion of organoleptic disguise  Match product colour to flavour * e.g. red for strawberry flavour  Requires additives * Not consumer friendly Suspension Three components * Solvent(s) * Continuous liquid phase * Solute(s) * Dissolved in solvent to modify behaviour * Solid phase * Non-dissolved material, discrete particles Ideal suspension Sediment – easily resuspended  Re-suspension – stable * Dose withdrawal  Particle size – uniform * Non-gritty (< 5 μm) Emulsion Three components * Solvent(s) * Continuous liquid phase * Solute(s) * Dissolved in solvent to modify behaviour * Disperse phase * Non-dissolved liquid, discrete particles Disperse phase - common in Topical creams Oil in water * Oil – disperse phase (not more than 60% v/v) * Active ingredient – cod liver oil * Water – continuous phase * Usual system  Water in Oil * Water – disperse phase * Oil – continuous phase * Difficult to process oil into the water phase Emulsifying agent * Surfactant * Polymeric agents  Viscosity enhancers  Density modifiers  Antioxidants  Masking fragrance

Answer 7

 Product ingredients * Risk – water, excipients, containers  Manufacturing * Equipment * Closed vessels, distribution, cleaning, filling  Distribution * Storage * Validated hold times * Ref Annex 9 EudraLex Vol. 4 * Consider Contamination Control Strategy Preservative * To deal with “in use” contamination * Not manufacture based contamination  Preservation * Complex area * Product * Suspension/emulsion * Container interaction

Answer 8

 Delivers drug as powder into lungs  May need to ‘load’ the drug  Reservoir or single dose  Need to consider moisture protection Formulation Ingredients  Drug and diluent  Micronisation of API  Particle size of API and excipients  Interactions between drug and diluent  Mixing and segregation  Potential for moisture uptake Actuation Device  Use of capsules, blister strips or chamber system  Mechanical disruption of powder  Moisture risk  Patient use impacts

Answer 9

 Used inverted (valve down)  Meters a dose, rather than sprays continuously  Drug and propellants inhaled into the lungs Formulation Ingredients  Particle size of API  Micronisation of API  Solubility characteristics of API – may need adjuvants  Surfactants aid suspension of drug substance  Surfactants aid valve lubrication  Propellants – CFC and HFA

Answer 10

 Crystals  Creaming and sedimentation  Agglomeration – fused aggregates that have broken away from their surface of origin to become entrained in the formulation with risk of occluding small atomisation orifices * Causing increased variability and/or OOS results in medication delivery data * Causing changes in the aerodynamic profile of the emitted dose How can we eliminate agglomerates or minimise their effect?  Avoiding creaming formulations  Use a bulking agent to minimise the risk of dose variability impact of agglomerates by co-aggregating with the active  Reduce exposure to moisture that helps to fuse the particles in agglomerates – e.g. pouching and / or use of nylon as a desiccant can have a positive impact Valve  Metal or plastic components  Elastomer components  Passivation of metal components  Cleaning  Design process e.g. tail off Canister  Coating Actuators/Spacers/BAIs/Dose Counters  Press and breathe actuators  Spacers – pros and cons  Breath Actuated Inhaler (BAIs) – design and complexity  Dose counters – FDA perspective Active Drug Substance  Particle size – Micronisation  Impurities and Degradation Products Surfactants  Concentrate manufacture Propellants and Adjuvants  Filtration and refrigeration Valve  Pressure filling/cold filling  Crimping process  Valve function testing Canister  ‘O’ ring  Canister marking and cleaning Filtration of all fluids to 0.2 micron – Annex 10  Cold filling  Pressure filling – single and two-stage  100% check weighing (Annex 10)  Optimisation/scale-up/validation – matrixing

Answer 11

Facilities  Air classification – minimum Grade D at point of exposure of product or clean components (Annex 10)  Moisture control  Water bath or Heat tunnel Actuator  Stem location  Critical dimension control in moulding  BAI Function testing Documentation  Complex process  Well designed documentation  Many similarities to MDIs Active Drug Substance  Moisture control  Freeze drying Diluent  Particle size  Powder flow characteristics  Many similarities to MDIs Active Drug Substance  Moisture control  Freeze drying Diluent  Particle size  Powder flow characteristics

Answer 12

 Identification – drug, propellants, adjuvants  Fill weight/number of doses  Moisture content  Drug content  Adjuvant content  Leakage  Suspension particle size – Malvern and Microscopy Release Testing  Valve delivery  Dose delivered – ex valve or ex actuator (through life)  Respirable dose – Andersen or New Generation Impactor  Impurity and Degradation Products  Foreign particulates  Microbial

Formulation Flashcards

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