Preformulation stability studies are the first quantitative assessment of chemical stability of a new drug.
This may involve
1. Stability study in toxicology formulation
2. Stability study in solution state
3. Stability study in solid state.
Stability Study in Toxicology Formulation:
A new drug is administered to animals through oral route either by
(i) Mixing the drug in the feed
(ii) In the form of solution
(iii) In the form of suspension in aqueous vehicle
• Feed may contain water, vitamin, minerals (metal ions), enzymes and different functional groups that may severely reduce the stability of the new drug. So stability study should be carried out in the feed and at laboratory temperature.
• For solution and suspension, the chemical stability at different temperature and pH should be checked.
• For suspension-state the drug suspension is occasionally shaken to check dispersibility.
Objective: Identification of conditions necessary to form a stable solution. Stability of a new drug may depend on:
(ii) Ionic strength,
(i) pH Stability Study:
(a) Experiments to confirm decay at the extremes of pH and temperature. Three stability studies are carried out at the following conditions:
• 0.1 N HCl solution at 90 Degree Centigrade
• Solution in water at 90 Degree Centigrade
• 0.1 N NaOH solution at 90Degree Centigrade
These experiments are intentionally done to confirm the assay specificity and for maximum rates of degradation.
(b) Now aqueous buffers are used to produce solutions with wide range of pH values but with constant levels of drug concentration, co-solvent and ionic strength.
All the rate constants (k) at a single temperature are then plotted as a function of pH.
(ii) Ionic Strength:
Since most pharmaceutical solutions are intended for parenteral routes of administration, the pH-stability studies should be carried out at a constant ionic strength that is compatible with body fluids. The ionic strength (μ) of an
isotonic 0.9% w/v sodium chloride solution is 0.15.
Ionic strength for any buffer solution can be calculated by
For computing, μ all the ionic species of the buffer solution and drugs are also taken into calculation.
Some drugs are not sufficiently soluble to give concentrations of analytical sensitivity. In those cases, co-solvents may be used. However, presence of co-solvents will influence the rate constant. Hence, k values at different co-solvent concentrations are determined and plotted against % of co-solvent. Finally, the line is extrapolated to 0% co-solvent to produce the actual k value (i.e. in pure solvent).
Drug solutions are kept in
(a) Clear glass ampoules
(b) Amber color glass container
(c) Yellow-green color glass container
(d) Container stored in card-board package or wrapped in aluminum foil – this one acts as the control.
Now the stability studies are carried out in the above containers.
The rate constant (k) of degradation reaction of a drug varies with temperature according to Arrhenius equation.
Buffer solutions were prepared and kept at different temperatures. Rate constants are determined at each temperature and the ln k value is plotted against (1/T).
Inference: The relationship is linear a constant decay mechanism over the temperature range has occurred.
A broken or non-linear relationship can change in the rate-limiting step of the reaction or change in decay mechanism.
Uses: Shelf life of the drug may be calculated.
e.g. Time Concentration of drug remaining
Conclusion: If the drug is sufficiently stable, liquid formulation development may be started at once.
If the drug is unstable, further investigations may be necessary.
Solid State Stability:
Objectives: Identification of stable storage conditions for drug in the solid state and identification of compatible excipients for a formulation.
• Solid state reactions are much slower, so the rate of appearance of decay product is measured (not the amount of drug remaining unchanged).
• To determine the mechanism of degradation thin layer chromatography (TLC),fluorescence or UV / Visible spectroscopy may be required.
• To study polymorphic changes DSC or IR-spectroscopy is required.
• In case of surface discoloration due to oxidation or reaction with excipients, surface reflectance equipment may be used.
1. Weighed samples are placed in open screw-capped vials and exposed to a variety of temperatures, humidities and light intensities. After the desired time samples are taken out and measured by HPLC (5 – 10 mg), DSC (10 to 50 mg), IR (2 to 20 mg).
2. To test for surface oxidation samples are stored in large (25ml) vials for injection capped with Teflon-lined rubber stopper. The stoppers are penetrated with needles and the headspace is flooded with the desired gas. The resulting needle holes are sealed with wax to prevent degassing.
3. After fixed time those samples are removed and analyzed.
Drug-excipient Stability Profile:
Hypothetical dosage forms are prepared with various excipients and are exposed to various conditions to study the interactions of drug and excipients.
• Melting point:
Each pure substance has a definite melting point. If not pure, the substance will exhibit a change in melting point. The pure substances have always higher melting points than their impure mixtures. This phenomenon is called melting point depression and commonly used to determine the purity of a drug substance.
• Unfortunately, many drug substances in use today are unpalatable and dosage forms containing such drugs (oral preparations) require the addition of flavors and/or colors.
Color is generally a function of a drug’s inherent chemical structure relating to a certain level of unsaturation.
• Color intensity relates to the extent of conjugated unsaturation as well as the presence of chromophores.
• Some compound may appear to have color although structurally saturated.
• The substance may exhibit an inherent odor, characteristic of major functional groups present.
• Odour greatly affects the flavor of a preparation or food stuff.
If taste is considered as unpalatable, consideration is to be given to the use of a less soluble chemical form of the drug.
The odour and taste may be suppressed by using appropriate flavors and excipients or by coating the final product.
Particle size can control variety of important factors :
– Dissolution rate
– Uniform distribution
– Lack of grittiness
Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field.
During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube