Pharmaceutical Stability

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Questions and Answers

What is the primary purpose of choosing a non-hygroscopic form of a drug?

To minimize the contact among the interacting drugs and water (correct)

To improve the solubility of the drug

To reduce the interaction between the drug and excipients

To prevent polymorphic transitions

Which of the following is NOT a physical degradation route?

Polymorphic transition

Crystallization of amorphous material

Hydrate/solvate formation

Chemical degradation (correct)

What happens to poorly soluble drugs when they are in an amorphous state?

They become more hygroscopic

They become more thermodynamically stable

They crystallize more quickly

They dissolve more readily (correct)

What is the consequence of incomplete drying after wet granulation and drying?

Seeding of the dihydrate Signup and view all the answers

What is the consequence of hydrate formation for carbamazepine?

Conversion to dehydrate in water Signup and view all the answers

Why is Enalapril incompatible with microcrystalline cellulose?

It causes dissociation of the amine maleate Signup and view all the answers

What is the consequence of rehydration of the dihydrate of carbamazepine?

Faster hydration at 93% RH Signup and view all the answers

What is the purpose of micellar inclusion?

To complex the drug with excipients Signup and view all the answers

What is the primary indicator of a product's stability?

Shelf life Signup and view all the answers

What is the consequence of a 10% reduction in the potency of an active substance under specific storage conditions?

End of shelf life Signup and view all the answers

What type of instability can lead to changes in solubility?

Physical instability Signup and view all the answers

What is the primary source of moisture in solid state reactions that can lead to instability?

All of the above Signup and view all the answers

What is the result of a solvate or hydrate losing its lattice solvent with time and temperature fluctuations?

Solid state reaction Signup and view all the answers

What is the purpose of altering the properties of solid drugs in stabilisation?

To increase the melting point Signup and view all the answers

Which type of instability can lead to degradation to toxic products?

Chemical instability Signup and view all the answers

What is the consequence of caking of suspensions in a product?

Formulation becomes unsuitable for application Signup and view all the answers

What type of instability occurs when chemical bonds are broken or formed?

Chemical instability Signup and view all the answers

Which of the following is NOT a condition that can cause hydrolytic degradation?

Presence of organic solvents Signup and view all the answers

What is the term for the process by which molecules of a drug or excipient are adsorbed from a solution onto the surface of solid particles?

Adsorption Signup and view all the answers

Which of the following types of chemical degradation is less common, but can occur in certain cases, such as with Ketoprofen?

Reduction Signup and view all the answers

What is the term for the formation of dimers, such as with Captopril and Amoxycillin?

Polymerisation Signup and view all the answers

Which of the following factors can increase the release of container components into a formulation?

All of the above Signup and view all the answers

What is the term for the process by which particles settle to the bottom of a container, leading to package failure?

Sedimentation Signup and view all the answers

Which of the following types of instability is caused by the absorption of light, leading to the breakdown of a drug?

Photochemical instability Signup and view all the answers

What is a key aspect of developing a stable formulation?

Thorough investigation of the intrinsic stability of the compound in preformulating stage of development Signup and view all the answers

What is the primary purpose of TGA guidelines?

To ensure the product meets physical and chemical specifications throughout its shelf-life Signup and view all the answers

What is an important aspect of a pharmacist's role in a pharmacy?

Checking storage conditions, expiry dates, and stock rotation Signup and view all the answers

What is an important aspect of a hospital pharmacist's role?

Advising on product storage conditions, TPN storage, and chemotherapy Signup and view all the answers

What is the purpose of replacing air with nitrogen in the headspace?

To prevent oxidation Signup and view all the answers

What is part of a pharmacist's role in a pharmacy?

Counselling patients, checking storage conditions, and advice on webster packs Signup and view all the answers

What is the role of nitrogen in the context of oxidation?

Stabilizing against oxidation Signup and view all the answers

Which of the following is NOT a susceptible group to oxidation?

Esters Signup and view all the answers

What is the primary mechanism of autocatalytic reaction in oxidation?

Peroxyl radical reinitiation Signup and view all the answers

What is the purpose of adding metal chelating agents in oxidation?

To stabilize against oxidation Signup and view all the answers

What is the result of photosensitisation in photodegradation?

Transfer of energy to other molecules to react Signup and view all the answers

What is the purpose of photostability testing?

To evaluate the stability of the drug in light Signup and view all the answers

What is the result of isomerisation in the context of vitamin A?

Conversion to inactive cis Vitamin A Signup and view all the answers

What is the effect of racemisation on the activity of L-hyoscyamine?

3x increase in activity Signup and view all the answers

Study Notes

Stability

Relates to various chemical, physical, and microbiological reactions that may change the original properties of a 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.

Types of Stability

Physical, chemical, and photochemical, microbiological stability.
One type of stability 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: aggregation, denaturation.

Solid-State Reactions

Occur in solution.
Major source of the solvent: residual moisture or solvent from wet granulation, moisture absorbed onto excipients, moisture in the capsule shell, melt of the drug itself or an ingredient in the formulation that has a low melting point, solvate or hydrate that loses its lattice solvent with time and temperature fluctuation.

Method of Stabilization

Altering the properties of solid drugs:
- Increasing melting point.
- Choosing a non-hygroscopic form (crystal or salt form).
- Reducing solubility by choosing a less soluble salt.
- Micellar inclusion.
- Complexation.
- Engineering of the particles (shape).
Physically separating the reacting species:
- Minimizing the contact among the interacting drugs and excipients, and water.
- Techniques: coating with polymers/microencapsulation, multi-layer tablet, tablet in a tablet, tablet in a capsule.

Main Physical Degradation Routes

Polymorphic transition (α, β, γ, forms), e.g., graphite to diamond.
Crystallization of amorphous material.
Hydrate/solvate formation/seeding effect.
Vaporization.
Sorption.
Particle sedimentation.

Chemical and Photochemical Instability

How to distinguish between chemical and photochemical instability: making or breaking chemical bonds à chemical instability.

Types of Chemical Degradation

Hydrolysis/fragmentation (biologics).
Oxidation.
Deamidation.
Isomerization.
Epimerization.
Reduction (less common, e.g., Ketoprofen =O -OH).
Polymerization (formation of dimers, e.g., Captopril and Amoxycillin).

Hydrolysis

If the drug is a derivative of carboxylic acid or contains functional groups based on this moiety (ester, amide, lactone, lactam, imide, or carbamate) then the drug is susceptible to 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.

Oxidation

Next most common pathway for drug breakdown.
Eliminated by the storage under anaerobic conditions.
Auto-oxidation.
Initiation à propagation à termination.
Stabilization against oxidation: nitrogen, carbon dioxide, heavy metal (iron, cobalt, nickel), temperature, inhibitors.

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: protect from light, oxygen, and temperature, add peroxide decomposing substance (sulfur), add antioxidant (e.g., ascorbic acid, ascorbityl palmitate), add metal chelating agents (e.g., EDTA).

Photochemical Degradation

Degradation when exposed to light – as a result, loss of potency.
Photodegradation – storage and use.
Photosensitization: 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).
Expose the finished product (tablet, capsules) in its final container and market pack to SSLS.
Stabilization: glass containers (color), coatings.

Isomerisation

Conversion of a substance to its geometric isomer (spatial re-orientation around double bonds).
Or optical isomer, racemization (D-L or L-D).

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: compliance, storage conditions, expiry dates, special conditions (extemporaneous, eye drops, Glyceryl trinitrate tablets).

As a Hospital Pharmacist…

Advice to nursing staff on product's storage conditions.
Advice on TPN storage and discarding date.
Advice on chemotherapy…etc.

Conclusions

Developing a stable formulation requires: through investigation of the intrinsic stability of the compound in pre-formulating stage of development, thermal and photo, against oxidation, relevant excipient compatibility studies, identify low-risk excipients, detailed stability studies of the formulations, accelerated conditions, understand the stability in formulations.

TGA Process

Purpose: To ensure the product meets physical, chemical, and microbial specifications throughout its shelf-life under the specified conditions.
Required in dossier: study design, test methods, commentary on results, conclusions and summary of claims.

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Description

This quiz covers the concept of stability in pharmaceuticals, including chemical, physical and microbiological reactions that affect a product's original properties during storage and transport.