Powders for Pharmaceutical use: API and excipients Part 1 Flashcards
What must be known about the pre-formulation of the drug?
To form the dosage form you need to know the chemical (structural), shape, solubility, and reactivity and physical (can be moved) properties of the API
Whats the pre-formulation steps for most drugs? (8 steps)
- Chemical Synthesis of drug
- Chemical and physical characterisation of drug (before that is pharmacological and toxicology trails on animals, clinical trials on humans)
- Pre-formulation study of drug
- Formulation- Drug substance and Add excipients
- Drug product with desirable features
- Scaling up
- Licensing of drug product
- Marketing of product
What are pharmaceutical powders? What are the pros and cons?
Intimate mixture of dry and finely divided API and excipients for use in either:
- Internal (oral) (sachet)
- Dispersed immediately prior to taking
- API unstable in solution
- Usually “non potent large doses of APIs”- antacids, laxatives, supplements
- External (topical)- dusting powder
Pros: Store them easier, longer expiry dates
Cons: have to watch out for the patient group with the dosage
What are the assumptions made about the API, and the methods to analyse and the excipients?
API structure is known and “pure”
- API is made in bulk for pre formulation and formulation studies
- Used to detect and identify any impurities and degradation products
- Qualitative and quantitative analysis- example: NMR and chromatography
- BP specification will include any acceptable limits on impurities
- Excipients we use are of pharmaceutical grade- lactose, microcrystalline cellulose- used to make it into a proper product
During pre-formulation, what is done to look at the API physical and chemical properties?
Look for a basic understanding of the nature of the API?
- How it behaves alone, and how it interacts with excipients
Chemical synthesis is done as the chemistry affects the material properties- example: different salt forms have different solubilities
What is considered about the chemical stability of drug in the body and the environment?
Early appreciation of the effects of:
- Temperature (affect sterilisation method)
- pH (body fluids- stomach)
- Moisture (packaging)
- Oxygen (manufacturing stages)
- Light (storage and packaging)
What ways can chemical stability be tested?
Accelerated stability testing is also useful:
- use of high temperatures
- use of high humidity
What is considered about the soubility of the drug in the body and the environment?
- All APIs must have some aqueous solubility for therapeutic effect
- Very poorly soluble APIs give erratic or incomplete absorption
- Solubility should be checked over a range of temperatures (5 to 50 degrees) and pH (2-8)
Can dramatically change solubility by using different salt forms
What is considered about the crystal form of the drug in the body and the environment?
- APIs in the solid form can either be:
- Crystalline
- Amorphous (not a regular molecular lattice arrange, moving around interacting with other things)
- Polymorphs- crystalline API that exist in more than one crystal form with different crystal packing arrangements - They all have different physicochemical and mechanical properties: solubility, stability, dissolution rate, melting point
- It is vital that the polymorphic form of the API that’s formulated is known and consistent: different batches do not consist of different polymorphs
Whats the difference between a longer polymorph and a shorter one?
- Longer one is more likely to break
2. Shorter one is less likely to break
What is polymorphism?
The different ways to fit the molecule together
Example: Testosterone has 4 polymorphs that melt at different temperatures.
What is a polymorph and why is it so important in drug making?
- Polymorphs- crystalline API that exist in more than one crystal form with different crystal packing arrangements
- So important as each polymorph can be more or less stable than the other, can dissolve rapidly or have a more rapid dissolution etc.
How does polymorphism impact on solubility?
- Solubility:
- the most stable polymorph is the least soluble but its use is still preferred for stability reasons
- Amorphous solids (not crystalline)- tends to be more soluble than the crystalline equivalents and much less stable and not widely used
How does polymorphism impact on dissolution rate?
- The rate of dissolution of a solid is roughly proportional to its solubility
- Good dissolution can aid bioavailability, slow dissolution, can greatly reduce it (drug passes through GIT before it can dissolve)
How does polymorphism impact on patent protection?
- It is possible to not only patent a chemical but also its physical form
Example: GSK patents forms 1 and 2 of ranitidine hydrochloride
