Pre-formulation Reformulation Of Powders Flashcards
Define pre-formulation
Preformulation is a branch of pharmaceutical science that utilises biopharmaceutical principles in the determination of physico-chemical properties of a drug substance
-Difference between a drug substance and product is that- Substance= API; product= finished dosage form
What are the goals of pre-formulation
- To choose the correct drug substance
- Evaluate and understand it’s physical properties
- Generate a thorough understanding of the materials stability data under various conditions, leading to the formulation of optimal drug delivery systems
- Determine drug compatibility with a various range of excipients
Preformulation
- This is done after an new chemical entity has been discovered
- First learning phase in dosage form development
- fundamental physical and chemical properties
- Only a small quantity of drug substance available (mg)
Planning and documentation of manufacturing of a drug
Put in phases when you have an audio
- Bio-pharmaceutics -> preformulation (characterise drugs) ->
- Product design (product profile and critical quality parameters) ->
- Product optimisation (quantitive formula, raw material- develop process for formulation of product) ->
- Process design (process outline, equipment/ facility definition) ->
- Process optimisation (In process controls, product specification) —>
- Scale up for clinical trials —>
- Scale up for commercial production —>
- Process validation —>
- Manufacture launch stock
Drug characterisation (pharmaceutical profiling)
- Assay- UV, HPLC, TLC (impurities)
- Solubility (aq.; pKa; salts; solvents; partition co-efficient; dissolution)
- Melting point
- Stability
- Microscopy
- Powder flow (bulk density, angle of repose)- powder properties
- Compression properties
- Excipients compatibility
Analytical preformulation
- Identity- NMR, IR, UV, DSC, TLC- structure and functional groups
- Purity- moisture content, inorganic and organic impurities, DSC
- Assay- UV, HPLC
- Quality- appearance, odour, colour, mtp
- All the above used to confirm structure and purity
Solubility
-Only a small quantity of a drug substance is available for preformulation studies (50mg)
-Compounds with solubility less than 1%w/v (pH 1-7 at 37C=BODY TEMP) potentially have bioavailability issue = decreased dissolution
+NB- we also do studies at 4’C for physical stability data
Potential solution
-Solubility in the range of 1-10mg/ml- salt formation desirable (only possible for ionisable drugs)
-Alternatively liquid filling in capsules e.g. neutral molecules, steroids etc
Solubility continued
- Intrinsic solubility (Co)- the fundamental solubility in an unionised state
- Solubility measured at 2 temperatures- 4C (to support physical stability and short-term storage) and 37C for (biopharmaceutical evaluation)
- Solubility data sheds light on pKa and formulation approach
pKa
-75% of all drugs are basic
-20% are weak acids
-5% non-ionic
Why is pKa useful?
-Used to maintain solubility by altering pH of solution
-Formation of appropriate salts for the poorly soluble parent drug
-pH at which 50% of the drug is ionised- this is important because as the drug becomes more ionised = increased solubility= more polar interactions
-For acid drug, 2 pH units above its pKa = drug is fully ionised
-For acid drug 2 pH units below pKa= drug fully unionised (opposite for basci drugs)
Salt formation
- Salts of strong acids/bases are freely soluble but suffer from high hygroscopically leading to instability in tablet/capsule formulation
- Weaker acids/bases used to form salts (e.g. maleate, acetate, aluminium)
- Ibuprofen lyseine- faster acting because the salt dissolves faster therefore peramtion and action occurs faster
- When inhalation we pick the least soluble salt form- we want the drugs to work locally on the lungs- if the drug is highly soluble more drug will enter systemic circulation
Impact of salt formation
- Lowers intrinsic pH thereby increasing solubility exponentially
- Dissolution rate of salt higher than parent drug
- However, alteration insolubility/ dissolution may affect bioavailability
Solvents
- Water is commonly employed solvent
- However aqueous instability is sometimes an issue (chlordiazepoxide HCL is hydrolysed)
- Water-miscible solvents used instead:
- Water miscble solvents used instead: to improve solubility/ stability ; in analysis for extraction and separation e.g. methanol;
- What is QbD- quality by design- this is guideline whereby quality assessments and monitoring are incorporated throughout the pharmaceutical process (looking at broad context e.g. effect of moisture content 8-15%)- if we demonstrate it is safe between 8-15% we have more flexibility as oppose to having a set <10%
- Preformulation characteristics of temazolamide
- Elixir or emulsion- if drug is poorly soluble but can be mixed with alcohol and water elixir can be used
Partition co-efficient (K0w)
-Definition: the solvent- water quotient of drug distribution
-Drug distribution between polar and non polar environment
Uses
-Gives information on aqueous and mixed solvent solubility
-Drugs absorption in vivo-
-Choice of column (HPLC) or plate (TLC)
-Octanol/water partition most commonly employed- we see how the distributes (in polar or non polar)- shows us how it would distribute in vivo also tells us what solvent is suitable
-Method: shake flask method
Drug assayed in aqueous phase of the mixture
-K0w=(sumC-Cw)/(Cw)
-C= conc in aqueous phase before partitioning
-Cw= conc after partitioning
Dissolution
K1= rate constant
Cs= solubility/ concentration in sink condition
A=Surface area
-Dissolution rate of drug is important where it is the rate limiting step in absorption
-When dissolution controlled solely by diffusion. rate proportional to the saturated conc of the drug in solution
2 types
-Intrinsic dissolution rate (mg cm2 min-1)= how much drug dissolves over time
-Total dissolution (mg/ml)
Intrinsic dissolution rate (IDR) =how much is dissolved in saturated solution
-Independent of formulation effects and measures intrinsic properties of drug (IDR=K1 Cs)
Total dissolution
-Exposed surface area cannot be controlled as disintegration, disaggregation and dissolution proceed
dc/dt=A/V K1 Cs
Common ion effect
-Common ion significantly reduces the solubility of a slightly soluble electrolyte
-Indicates weather the contents of the GI will effect drug dissolution
-With a narrow INR drug, if the drug begins to increase dissolution = toxicity or underdose if decreased dissolution
2 types
-Salting out: Due to removal of water molecules as solvents i.e. hydration of other ions
-When the drug is precepitated out due to the effects of ions present
-Salting in: Due to larger anions which open the structure of water e.g. benzoate, salicylate
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