The stability of pharmaceutical products plays an important role in the effectiveness of drug products and patient safety. An unstable pharmaceutical product can degrade and produce toxic byproducts those can lead to fatal consequences.
Therefore, stability testing is done at every stage of pharmaceutical product development. This article outlines the strategies to overcome the challenges in pharmaceutical product stability.
1. Temperature: High temperature encourages chemical activity. Within the drug product, temperature can break down the drug molecules and forms an entirely different byproduct which is called drug impurity.
2. Moisture: In the presence of excess moisture due to higher humidity, the product can react with water and lead to hydrolysis. It creates byproducts that may be harmful for human consumption.
3. Light: Light is another factor that can lead the product towards degradation. Light, especially ultraviolet light can cause photolysis, in which the product starts oxidizing producing byproducts.
4. Oxygen: Oxygen is present in atmospheric air that reacts with ingredients of the formulation. Some ingredients are susceptible to oxygen and produce degradation products in the presence of air.
2. Drug and Excipient Interaction: In any pharmaceutical formulation drug and excipients are mixed. Sometimes this drug and excipient interaction can lead to degradation of ingredients (API or excipient).
3. Packaging Material: Drug formulation can start degrading after interaction with packaging material. Sometimes moisture content may penetrate into the packaging and can lead towards degradation.
During the formulation development, formulation studies such as pH, solubility, thermal and photostability and compatibility with the excipients can help to protect the product from these unwanted degradations. These studies can help to formulate more stable products.
1. Buffers: As we know, pH plays an important role in making the product stable because in acidic or basic conditions reactions become faster. The buffers are useful to keep the pH of pharmaceutical products stable. Citrate, acetate and phosphate buffers are widely used in liquid formulations.
2. Chelators: Chelators make the pharmaceutical ingredients stable by preventing their oxidation. These are also called antioxidants. EDTA is widely used for this purpose.
3. Stabilizers: Some experience like HPMC or PVP are added in the formulation to make other excipients stable. These help to improve the solubility as well as the stability of the product.
4. Moisture Trappers: Some silica desiccants are added in the packaging of moisture sensitive formulations. They absorb moisture from the packaging and help to make the moisture sensitive formulation stable.
Formulation optimization may require changing the form of API (like from sulfate salt to acetate salt), excipient or sometimes it is required to change the type of formulation to make the product stable and consistent.
1. Inert Condition Packaging: To prevent oxidation of the formulation ingredients, some sensitive products are packed in an inert environment. Nitrogen is filled with the product replacing the oxygen, it helps the product to prevent from oxidation and finally degradation due to oxygen.
2. Light Resistant Packaging: Light sensitive products are packed in amber colored glass bottles or UV-filtered plastic containers. It prevents the light sensitive products from degradation.
3. Moisture Proof Packaging: Moisture sensitive products are packed in alu-alu packaging and bottle packaging is packed with desiccant. This helps to make the containers moisture free and finally prevent degradation due to moisture.
4. Single Dose Packaging: Packaging as a single unit dose is also useful to prevent the exposure of drug products to environmental conditions. Products packed in the bottles having many units will allow to expose these daily during the use. Single dose units are consumed separately without any exposure of other units into the environment.
1. HPLC: HPLC is widely used for the analysis of pharmaceutical products. It helps to identify the degradation products within the formulation.
2. UV Spectrophotometer: UV spectrophotometer is used to determine the photostability of the pharmaceutical products. It is also widely used in pharmaceutical manufacturing facilities.
3. Karl Fischer Titrator: Karl Fisher Titrator is used to determine the moisture content in pharmaceutical ingredients as well as the final product. It is the most efficient and widely used method to determine the moisture content.
4. Simultaneous Thermal Analysis: Thermogravimetric analysis and differential scanning calorimetry are used to determine the thermal and physical stability of the product.
These studies must be carried out for the final product and companies must conduct ongoing stability monitoring to fulfill the regulatory requirements throughout the product life cycle.
2. Microencapsulation: Microencapsulation is used to create a protective barrier around the API to reduce the exposure of the drug to environmental factors. It helps to make the product more stable during its exposure to the environment.
3. Hot Melt Extrusion and Solid Dispersion: By this technique, we can improve the solubility and chemical stability of products having less water-soluble APIs.
4. Cyclodextrin Complexes: These complexes are also helpful in improving the solubility and protecting the drugs from degradation due to interaction with the other ingredients of the formulation.
When none of the above techniques works, finally the product is reformulated. This may involve the modification of drug product form, changing in excipients or sometimes altering the API to a more stable derivative. The change in formulation should always be guided by the experienced persons who actually faced the formulation stability issues of the product and only they can suggest a better alternative to get a stable product.
Adaptation of new technologies and regulatory requirements can help in the formulation to get a safe and quality product. Stability of products is not just a regulatory requirement but it is essential to ensure the delivery of a safe and effective product to patients.
Therefore, stability testing is done at every stage of pharmaceutical product development. This article outlines the strategies to overcome the challenges in pharmaceutical product stability.
Understanding the Root Cause of the Instability of Product
It is not an easy task to identify the actual cause of product degradation because there are several factors those can affect pharmaceutical product stability. Sometimes environmental factors are responsible while in other cases some chemicals or microorganisms plays their role in drug products degradation. Following are some important reasons for instability of drug products.
A. Environmental Factors
1. Temperature: High temperature encourages chemical activity. Within the drug product, temperature can break down the drug molecules and forms an entirely different byproduct which is called drug impurity. 2. Moisture: In the presence of excess moisture due to higher humidity, the product can react with water and lead to hydrolysis. It creates byproducts that may be harmful for human consumption.
3. Light: Light is another factor that can lead the product towards degradation. Light, especially ultraviolet light can cause photolysis, in which the product starts oxidizing producing byproducts.
4. Oxygen: Oxygen is present in atmospheric air that reacts with ingredients of the formulation. Some ingredients are susceptible to oxygen and produce degradation products in the presence of air.
B. Drug Related Factors
1. Drug Impurities: Some impurities are always present in pharmaceutical formulations. These impurities can accelerate the degradation of pharmaceutical ingredients producing more degradation products.2. Drug and Excipient Interaction: In any pharmaceutical formulation drug and excipients are mixed. Sometimes this drug and excipient interaction can lead to degradation of ingredients (API or excipient).
3. Packaging Material: Drug formulation can start degrading after interaction with packaging material. Sometimes moisture content may penetrate into the packaging and can lead towards degradation.
During the formulation development, formulation studies such as pH, solubility, thermal and photostability and compatibility with the excipients can help to protect the product from these unwanted degradations. These studies can help to formulate more stable products.
Formulation Optimization and Excipient Selection
Once the root cause is identified, the formulation optimization strategies are implemented. This involves choosing the right type of pharmaceutical excipients, which can enhance the formulation stability without changing product specifications. Following are some options to try.1. Buffers: As we know, pH plays an important role in making the product stable because in acidic or basic conditions reactions become faster. The buffers are useful to keep the pH of pharmaceutical products stable. Citrate, acetate and phosphate buffers are widely used in liquid formulations.
2. Chelators: Chelators make the pharmaceutical ingredients stable by preventing their oxidation. These are also called antioxidants. EDTA is widely used for this purpose.
3. Stabilizers: Some experience like HPMC or PVP are added in the formulation to make other excipients stable. These help to improve the solubility as well as the stability of the product.
4. Moisture Trappers: Some silica desiccants are added in the packaging of moisture sensitive formulations. They absorb moisture from the packaging and help to make the moisture sensitive formulation stable.
Formulation optimization may require changing the form of API (like from sulfate salt to acetate salt), excipient or sometimes it is required to change the type of formulation to make the product stable and consistent.
Improvement in Packaging and Storage
Packaging plays an important role in protecting the pharmaceutical product from environmental conditions like humidity, light and air. Depending on the type of formulation various types of packaging are used.1. Inert Condition Packaging: To prevent oxidation of the formulation ingredients, some sensitive products are packed in an inert environment. Nitrogen is filled with the product replacing the oxygen, it helps the product to prevent from oxidation and finally degradation due to oxygen.
2. Light Resistant Packaging: Light sensitive products are packed in amber colored glass bottles or UV-filtered plastic containers. It prevents the light sensitive products from degradation.
3. Moisture Proof Packaging: Moisture sensitive products are packed in alu-alu packaging and bottle packaging is packed with desiccant. This helps to make the containers moisture free and finally prevent degradation due to moisture.
4. Single Dose Packaging: Packaging as a single unit dose is also useful to prevent the exposure of drug products to environmental conditions. Products packed in the bottles having many units will allow to expose these daily during the use. Single dose units are consumed separately without any exposure of other units into the environment.
Use of Product Analysis Techniques
Robust analytical techniques are required to identify the degradation of products and to confirm the effectiveness of stability strategies. These techniques include1. HPLC: HPLC is widely used for the analysis of pharmaceutical products. It helps to identify the degradation products within the formulation.
2. UV Spectrophotometer: UV spectrophotometer is used to determine the photostability of the pharmaceutical products. It is also widely used in pharmaceutical manufacturing facilities.
3. Karl Fischer Titrator: Karl Fisher Titrator is used to determine the moisture content in pharmaceutical ingredients as well as the final product. It is the most efficient and widely used method to determine the moisture content.
4. Simultaneous Thermal Analysis: Thermogravimetric analysis and differential scanning calorimetry are used to determine the thermal and physical stability of the product.
These studies must be carried out for the final product and companies must conduct ongoing stability monitoring to fulfill the regulatory requirements throughout the product life cycle.
Use of Advanced Techniques and Product Reformulation
1. Lyophilization or Freeze Drying: Lyophilization or freeze drying is used to remove water content from heat sensitive products. It helps to stabilize the moisture sensitive products.2. Microencapsulation: Microencapsulation is used to create a protective barrier around the API to reduce the exposure of the drug to environmental factors. It helps to make the product more stable during its exposure to the environment.
3. Hot Melt Extrusion and Solid Dispersion: By this technique, we can improve the solubility and chemical stability of products having less water-soluble APIs.
4. Cyclodextrin Complexes: These complexes are also helpful in improving the solubility and protecting the drugs from degradation due to interaction with the other ingredients of the formulation.
When none of the above techniques works, finally the product is reformulated. This may involve the modification of drug product form, changing in excipients or sometimes altering the API to a more stable derivative. The change in formulation should always be guided by the experienced persons who actually faced the formulation stability issues of the product and only they can suggest a better alternative to get a stable product.
Adaptation of new technologies and regulatory requirements can help in the formulation to get a safe and quality product. Stability of products is not just a regulatory requirement but it is essential to ensure the delivery of a safe and effective product to patients.
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