Pharmaceutical Formulation and Excipients

Pharmaceutical formulation is a process of formation of pharmaceutical products (dosage form) by the use of Active Pharmaceutical Ingredients (APIs) with all necessary inactive ingredients (excipients); considering the factors of dosage form and becoming the final beneficial medicinal product. The process for optimizing and composition of the mixtures in a drug is called formulation.

Pharmaceutical formulation aims to transform APIs (Active Pharmaceutical Ingredients) into safe, efficacious, stable and user-friendly medicinal products. Pharmaceutical formulation involves appropriate selection of the excipient, determination of best dosage form and ensuring that the final products meet the compliances and regulatory standards. Pharmaceutical formulation is one of the core parts of drug discovery and also known as pharmaceutical dosage form. There is solid, liquid, gas and semisolid formulations intended to have different routes of administration according to patient need. 

Pharmaceutical Formulation development processes are:

Pre-formulation Studies: Physicochemical Characterization and compatibility studies

Formulation Design: Excipient Selection and Dosage form Selection

Formulation Optimization: Experimental design and Pilot scale production

Stability Testing: Accelerated stability testing and Long-term stability testing

Scale-up and Technology transfer: Process Scale-up and Technology Transfer

Active Pharmaceutical Ingredient (API) vs. Excipients

API is the drug substance that is a biologically active component responsible to produce a therapeutic effect and treats disease or medical conditions. It can be derived from natural sources or synthesized chemically. API is subjected to stick with the regulations and quality control to ensure they are pure, potent and safe for use in pharmaceutical dosage form whereas pharmaceutical excipients are pharmacologically inactive substances that are used mainly as a carrier of the API in the drug. Excipients are responsible to provide bulkiness to the formulations, facilitate pharmacodynamics activities, provide stabilities and prevent deterioration of drugs. Additionally, API lacks physical properties which are required for safe, accurate and effective delivery, excipients are used to produce long term stable products, uniform and patient-compliance medication.

Ideal characteristics of Excipients should be:

• chemically and physically inert,
• Non-toxic,
• Compatible with drugs, other ingredients and packaging materials,
• Organoleptically acceptable,
• Economic
• No therapeutic activities of its own.

Similarities VS Differences

API and excipient both are raw materials which work together to define the final dosage form. Both help in stability and protection; API constitutes an active agent which helps to ensure drug effectiveness and excipient helps to prevent the API from degrading during storage conditions. Compatibility of both is highly mattered for safe and efficacious medication. 

The Importance of Pre-formulation Studies

Pre-formulation is the first stage of rational development of dosage form. Pre-formulation studies assists scientists in screening lead active pharmaceutical ingredients based on their physiochemical and biopharmaceutical properties. Pre-formulation drug discovery is development of the drug until registration. There are four pre-formulation studies and the importance are:

• Analytical parameters: It helps to ensure the identity, purity, quality and strength of the API and excipients.

• Molecular structure determination: Helps in determining the chemical structure of a compound and ensures the identity and purity. Infrared Spectroscopy, UV- visible spectroscopy, Nuclear Magnetic Resonance and Mass Spectrometry are used in structural determination.
• Quantification: Helps to determine the drug concentration in a mixture of drug substances and formulation. HPLC, TLC, UV Spectrophotometry and Titrimetric methods are used in quantitative analysis.
• Purity: Helps in determination of Related Substance, Residual Solvent, Heavy Metals, Synthetic Impurities and degrading of a drug substance.
• Physical parameters: Determination of physical parameters helps to analyze the drug performance and its compatibilities.
• Physical Analysis: Particle Size & Shape, Melting Point, Hygroscopicity, Thermo-gravity, Bulk Density & Tapped Density, Flow Properties, etc. are the parameters for identification of physical analysis.
• Pharmaceutical parameters: It helps to select the suitable excipients and maintain the performance and stability of a product throughout the shelf-life.

• Biopharmaceutical Properties: Solubility, Partition Coefficient, pKa, Dissolution Rate, etc. helps in improving the therapeutic effect and dosage form selection.
• Chemical compatibility: Drug- Drug interaction, Drug- Excipient interaction and Excipient- Excipient interaction may produce incompatibility toward stability. So, selection of substances should be made in such a way it will prevent degradation, maintain potency and extend shelf life.
• Regulatory stability: ICH guideline helps to determine the shelf like, determine storage condition and ensure the regulatory compliance
• Physiochemical parameters: This property helps to ensure the product safety and efficacy by determining the formulation selection and packaging selection.
• Chemical stability & physicochemical property: Helps in maintaining the drug’s true nature and determining if there is any source of degradation. Natural degradants and ADME properties of drug substances.

Classification of Excipients

Pharmaceutical excipients are based upon origin and functions.

Excipients based on their origins:

Excipients based on their functions:

Diluents, Binders, and Fillers

Diluent and fillers are two different terms but work the same. They are added to increase bulk so as to make the dosage form of particular size & weight, to enhance the flow of powder and to allow easy manufacturing. For example: 

• According to Chemical Nature

Organic materials: Dextrose, Lactose, Mannitol, Sorbitol, Starch, Sucrose

Inorganic materials: Calcium Phosphate II & III, Calcium Sulphate and Calcium Carbonate

• According to Solubility

Insoluble: Starch, Calcium Phosphate II & III, Calcium Sulphate and Calcium Carbonate

Soluble: Dextrose, Lactose, Mannitol, Sorbitol, Sucrose

Binders/ Adhesive are ‘glue’ used to adhere powder together and prepare granules which helps in tablet production. If binder is used in more than desired quantity, makes a hard tablet which will not disintegrate easily. So, to prevent undesirable forms, binders are used in recommended quantities. For example: Natural binders: Acacia, plant or animal gelatin and Tragacanth (Solution for 10-25% Concentration) and synthetic binder: Cellulose derivatives (Methyl cellulose, Hydroxy propyl methyl cellulose, Hydroxy propyl cellulose, ethylcellulose), Polyvinylpyrrolidone (PVP) 2% concentration, Sodiumalginate and Gelatin (10-20%).

Disintegrants and Superdisintegrants

Disintegrants help to release active drugs from the tablet and allow rapid dissolution. This is a substance or mixture of substances added to a tablet formulation to facilitate its break up or disintegration when it comes in contact with GI fluid after administration. Some disintegrants function by drawing water into the tablet, swelling and causing the tablet to burst apart and some acts by porosity and capillary action.

 Disintegrating agents are usually mixed with active ingredients and diluents prior to granulation which helps in disintegration of granules in smaller particles and another portion is added during lubrication which helps in breaking tablets into granules. For example: Starch & its derivatives (5-20% of tablet weight), Alginates, Sodium starch glycolate, tartaric acid, etc. Disintegration time of tablets can be affected by disintegrants used and other factors such as binder, hardness and lubricants.

Superdisintegrant swells up to ten fold within 30 seconds when contact with water. They are used in dispersible tablets and tablets which need to disintegrate fast. Greater disintegrating efficiency and mechanical strength are seen even in low concentration of superdisintegrants. On contact with water, super-disintegrating agents swell, hydrate, change volume or form and produce a disruptive change in tablet. Example of superdisintegrants: Crosscarmellose (cross-linked cellulose), Crosspovidone [cross-linked povidone (polymer)], modified starches (Sodium starch glycolate).

Lubricants & Glidants 

Lubricants and Gladiants are anti- frictional/ anti- adherent agents. Lubricants are intended to prevent adhesion of the tablet materials to the surface of dies and punches, reduce inter particle friction and may improve the rate of flow of the tablet granulation whereas glidants are intended to promote flow of granules or powder material by reducing the friction between the particles. For examples: 

• Lubricants: Stearic acid, Stearic acid salt (Stearic acid, Magnesium stearate), Talc, etc.
• Glidants:  Corn Starch (5-10% conc.), Talc (5% conc.), Silica derivative (Colloidal silicas such as Cab-O-Sil, Syloid, Aerosil in 0.25-3% conc.), etc.

Preservatives and Antioxidants

Preservatives are a substance which is used to prevent bacterial growth and degradation of preparations. Preservatives interfere with the growth, multiplication and metabolism of the micro-organisms. Selection of preservatives should be in such a way that it is effective in low concentration, compatible with all other ingredients, doesn’t affect the specification of other ingredients and are nontoxic, non-irritant and non-sensitizing. For example: Methyl paraben, propyl paraben, benzyl alcohol, chloroxylenol, etc.

Antioxidants are reducing agents that help to prevent oxidation of oxygen sensitive substances by blocking an oxidative chain reaction or reducing the prone oxidation site. Antioxidants are used in low concentrations (0.2% w/w) with conjunction with chelating agents or without conjunction.  For example: Ascorbic acid esters, butylhydroxy anisole, tocopherols, hydroxy toluene, EDTA, sodium sulphite, sodium metabisulphite, etc.

Flavoring and Coloring Agents

Flavoring agents help to provide flavor and mask the unpleasant taste of drug substance. For the chewable tablet flavor oil is used and sweetening agents like sugar, mannitol, Saccharine (artificial sweetener which is 500 times sweeter than sucrose), Aspartame (artificial) are used in liquid formulations with other flavoring agents such as Menthol, Cardamom, Pineapple, Orange, etc.

There are two types of coloring agents: supra and lake. Supra is water soluble dye and lake is oil dispersible dye. The use of colors and dyes in a tablet has three purposes: Masking of off-color drugs, Product Identification, Production of more elegant products, etc. All coloring agents & flavoring agents must be compatible and should be approved and certified by the FDA. For example: yellow color from sunset yellow, green color from tartrazine, blue color from brilliant Blue or Indigo carmine, red color from erythrosine, Eosin Y, etc.

Stability Testing and Shelf Life (ICH Guidelines)

The mixtures of API and excipients are supposed to be stable in any storage conditions such as exaggerated heat, light and humidity. To detect the incompatibility of raw material stability testing is done. Incompatibilities are detected by various signs such as appearance of precipitate, insignificant decrease in assay and decrease in the concentration of intact drug. 

According to ICH guideline stability testing falls under Q1A to Q1F subcategory of Quality topic i.e. Q1A (R2): Stability Testing of New Drug Substances and Products

Q1B: Stability Testing: Photo-stability Testing of New Drug Substances and Products

Q1C: Stability Testing for New Dosage Forms 

Q1D: Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products

Q1E: Evaluation of Stability Data

Q1F: Stability Data Package for Registration Applications in Climatic Zones III and IV 

Shelf- life is the time from manufacture until the original potency of active constituent has been reduced by 10%.  A series of tests are designed to obtain information on the stability of a pharmaceutical product in order to define its shelf- life and utilization period under specified packaging and storage conditions (expiry date). There are two types of stability tests to estimate the shelf life.

• Real Time Stability Testing

Whether real time stability studies are performed at 25 °C ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is determined by the climatic zone in which the FPP is intended to be marketed. Real time stability testing (Long-term testing) should cover a minimum of six or twelve months at the time of submission and should be continued for a period of time sufficient to cover the proposed shelf life.

 For products with a proposed shelf-life of at least 12 months, the frequency of testing at the long-term storage condition should normally be every three months over the first year, every six months over the second year and annually thereafter through the proposed shelf-life.

• Accelerated Stability Testing

At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g. 0, 3 and 6 months) should be documented from a 6 months study. The storage conditions for Accelerated stability testing are 40°C ±2°C/75% RH ±5% RH.

The purpose of accelerated stability testing is to assess product stability within a short period of time.

Importance of Stability Test

• To study how the quality of an API or Finished Pharmaceutical Product (FPP) varies with time under influence of various environmental factors such as temperature, humidity and light.
• To find the product related factors that influence the stability: such as physiochemical properties of API & excipients, dosage form & its compositions, manufacturing process, etc. 
• To find the possible degradation of an API in reaction to the excipients or packaging materials.
• To find out a re-test period for API or shelf- life of finished product.

Factors Affecting Stability

• Temperature: The rate of chemical reaction is directly proportional to the temperature. Temperature effects on chemical factors of drug products. According to Arrhenius, the rate of chemical reaction is doubled by rising 10 degree Celsius in temperature which causes reaction to occur rapidly and time of reaction is reduced by a factor of 2.

Arrhenius equations: k=Ae^(-Ea/RT)

Where k= specific rate constant, A= frequency factor or Arrhenius factor, Ea= energy of activation, R= ideal gas constant (1.987 cal/mol.deg), T= absolute temperature

Room Temperature: 25℃-30℃

Cold Temperature: 2℃-8℃

Freezing Temperature: -20℃ to -10℃

• Light: Light plays a vital role in product deterioration via energy or thermal effect, which causes the oxidation of substances present in the drug formulation. Photolabile (photosensitive) drugs such as riboflavin, tetracycline, chlorpromazine undergo potency degradation. The photochemical decomposition of pharmaceuticals is due to the absorption of sunlight particularly in the spectral region of visible blue, violet and ultraviolet wavelengths (500 to 300nm). To prevent photo-degradation the storage condition for each drug should be maintained such as use of amber colored bottles, storing the product in dark, packaging in cartons, coating of tablets with polymer films, etc.
• PH: Acidic and alkaline pH influences the rate of decomposition of most drugs. Most drugs are stable at pH between 4 and 8. Buffers are mainly used to maintain pH.
• Concentration: The rate of degradation is constant for the same drug. So, the ratio of amount of degraded drug and total amount of drug in concentrated solution is less than that of diluted solution.
• Moisture: Moisture absorption or its presence increases the weight of the product, dilutes the dose, and decreases the potency. The microbial growth is also a potent risk of presence of moisture. A preventive measure to avoid the instability is to store such products in well closed containers. 
• Water: Drug substances with a functional group of amide, imide and esters undergo hydrolysis because of its ionic nature. Ionic species such as H+ and (OH)- proceed hydrolysis faster than neutral molecules. Hydroxyl ions catalyze hydrolysis by about 100 to 1000 times more actively than hydrogen ions. To prevent hydrolysis one of these may be the solutions; pH of the drug at minimum or ideal choice of solvent selection or modification of chemical structure or use of complexing agents or production of insoluble form of drug.
• Oxygen and oxidation: Aldehydes, amines, ethers, phenols, thiols, thioethers, and unsaturated fat/oil functionalities are particularly prone to oxidation. To prevent oxidation, reducing agents are used. Some of them are Potassium metabisulphites, Sodium metabisulphites, etc.
• Type of dosage form: Among the three dosage forms solid dosage forms are more stable.
• Drug Incompatibilities: Stability may be affected due to drug-drug interactions or drug- excipient interactions or drug- container reaction. Sometimes there is undesirable interaction of excipients and leads to failure on desired output but some modifications to excipients enhance the desirable outcome. For example modified excipients improve process ability such as flow properties, compressibility, and disintegration & dissolution profiles. Packaging should be selected in such a way that it adequately preserves the integrity of products. The package should be inert in nature, should protect the product from external environmental conditions, etc. 
• Other Factors: Other chemical characteristics of drugs such as ionic strength, dielectric constant are also the factors affecting stability.

Conclusion

Formulation is the process for optimizing and composition of the mixtures in a drug. Pharmaceutical formulation development is a multi-step and complex process that plays a significant role in the success of drug products. Excipients are the omissible components for a medicinal product which must be ideally inert, safe and stable. In order to avoid the drug- excipient, excipient- excipient interactions and packaging material- excipient reaction various stability testing procedures are carried out. This includes subjecting the excipients in the extreme conditions of temperature and humidity according to the climatic zone. Before using any new excipients it is important to recognize the need of excipients in various complex delivery systems and their safety assessments. Documentation of each and every step involved from selection of API and excipient to their dosage form criteria should be done.

References

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2. Drug Formulation: The Key to Successful Pharmaceutical Innovation. (2024, July 30). Adragos Pharma. https://adragos-pharma.com/drug-formulation-the-key-to-successful-pharmaceutical-innovation/#what-is-drug-formulation

3. Rowe, R., Sheskey, P., & Owen, S. (2006). Handbook of Pharmaceutical Excipients Fifth Edition.

https://www.gmpua.com/RD/RD/HandbookPharmaceutical%20Excipients.pdf

4. ICH. (2025). INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED GUIDELINE STABILITY TESTING OF DRUG SUBSTANCES AND DRUG PRODUCTS Q1. https://database.ich.org/sites/default/files/ICH_Q1EWG_Step2_Draft_Guideline_2025_0411.pdf

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