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
-
Melting point
Can be measure using 3 different techniques
-Capillary melting- to determine melting range- good because only need small amount- at the point that it melts we see the drug bubbling
-Hot stage microscopy- consists of heated sample stage
-Differential scaling calorimetry (DSC)- gives additional info including polymorphs
Uses
-Melting point determination and phase changes shed light on polymorphism
-Also used for excipient selection
DSC trace
-If we are presented with a DSC ALWAYS find the Y axis- to determine which way endo and exothermic
- Heat 2-3mg and we are capturing heat profile over a temp range
- 2 pans (one with drug and one empty- reference)
- Starts isothermal
- Starting transient (goes more endothermic)
- Glass transition (goes more endothermic)- step change seen in amorphus material- the glassy cage melt and molecules can move in any direction
- Crystallisation (DeltaHc)- greatly exothermic- where molecules are heated to a certain point they can arrange themselfs in an ordered crystal fashio
- Fusion (area= heat of fusion delta Hf) the area also equals melting point ranges with the middle being the mpt
- End transient- then return to isothermal
Polymorphism
-A polymorph is a solid material with at least 2 different molecular arrangement that give different crystal species
Issues:
-Solubility, mpt, density (different density= different flowability= less dosage uniformity), crystal shape, optical and electrical properties are different for each polymorph
-Species with highest mpt generally stable
In reformulation study the following need to be considered
- How many polymorphs exist?
- How stable are the metastable forms ?
- Can the metastable form be stabilised?
- What is the solubility of each form?
Pseudo polymorphism (solvates)
- Polymorphs obtained by recrystallising solvent
- presence of other solvents trapped inside
- Generally common with solvents such as water; methanol; ethanol; isopropanol
- If water trapped= hydrate
- Anything other than water= SOLVATE
- Can be distinguished from true polymorphs using hot stage microscopy
- Solvent bubbles around its bpt when microscope stage is heated= hydrate or solvate
Assay development
UV spectroscopy- relatively easy to set up and generate data
-Thin layer chromatography (TLC)- used to estimate impurity levels and also to establish the number of impurities
High pressure liquid chromatography (HPLC)
-Versatile technique
-Normal phase HPLC uses hydrophilic silica column
-Reverse phase HPLC uses hydrophobic silica columns (c18)
-Impurities and degradation products
Stability
Drug degradation occurs by 4 main process
- Hydrolysis
- Oxidation
- Photolysis
- Trace metal catalysis
Hydrolysis
-Most common cause of drug instability
-Hydrolytic reactions involve nucleophilic attack of bonds by water
Conditions that catalyse breakdown:
-Hydroxyl ions, H ions
-Heat, light
-High drug concentrations
Solutions:
-Use water miscible solvents to suppress ionisation
-Inclusion of buffers
Oxidation
-Occurs essentially due to light, trace metals or presence of O2
Solution
-Use of anti-oxidants
-Storage in amber coloured bottles
Photolysis
-Oxidation and sometimes hydrolysis catalysed by light
-Energy dependent on wavelength
Solution
-Storage in amber coloured bottles, Al foil wraps
Microscopy
Used in pre-formulation studies for
-Gives an estimate for particle size only gives mean
-Laser diffraction is better because it gives full profile in a given sample
-To determine crystal morphology (0.5-300mcm)
-Particle size analysis (0.5-50mcm)
Crystal habit can be modified in the following ways
-Excessive supersaturation e.g. prism changes to needle shape
-Cooling rate and agitation e.g. naphthalene- platy (rapidly cooled) and prisms (slow evaporation)
-Addition of co-solvents
Particle size analysis
-Influences dissolution rate
-Blend homogeneity in powders
Method for analysis
-Sieving
-Coulter counter
-Laser light scattering
Powder flow properties
-Bulk (tap) density and angle of repose important to ascertain powder flow properties
-Carr’s index is measure of bulk density
Carr’s index= tapped-poured density/ tapped density * 100
5-15= excellent
12-16= good
18-21 = fair to passable
23-35= poor
33-38= v.poor
>40= extremely poor
Angle of repose
-Angle of repose is the maximum angle of a stable slope determined by friction, cohesion and shapes of the particle
Excipient compatibility
- To promote consistent release
- To ensure required bio-availability
- To protect the drug from degradation
- DSC data helps in identifying interactions between drug and excipients
- Changes in melting point, peak shape, area, transition temperature signify interactions- any deviation in original thermal profile of the drug (when testing run the drug by itself as a reference)
Excipient compatibility
Drug + excipient (50% mix) –> if there is no interaction, this is the recommended excipients
-If there is an interaction –> TLC (show degradation products) –> significant breakdown –> if yes use an alternative excipient (if no breakdown then use this excipients)
Preformulation can be split into 2 sections
1)Drug characterisation- Generating physio-chemical properties
2)Analytical characterisation- analytical method to determine quality and quantity of the material
+HPLC- impuritie , degradation products
Method of determining pKa
- Measure solubility of the drug
- As the pH changes the solubility for the drug will also increase
- The solubility will then peak (at approx 2 pH levels above pKa)
- We get an S-shaped curve and the mid point will give the pKa
Method of determining pKa
- Measure solubility of the drug
- As the pH changes the solubility for the drug will also increase
- The solubility will then peak (at approx 2 pH levels above pKa)
- We get an S-shaped curve and the mid point will give the pKa
Tenzolamide pre-formulation data
- Stable in acidic conditions
- Mpt= 212’C
- Not a salt so has good solubility
- MW= 194.154 g/mol
- pH stability is an issue= instable in alkaline information
- Soluble in DMSO
Definition of a crystal
- Specific arrangement of ordered units (lattice)
- Amorphous materia - is a random arrangement of atoms/molecules held together in a glassy cage-
