Pre-formulation Studies

Almost all drugs are marketed as tablets, capsules, or both. Prior to the development of these major dosage forms, it is essential that certain fundamental physical and chemical properties of the drug molecule and other divided properties of the drug powder are determined. This information decides many of the subsequent events and approaches in formation development. The first learning phase is known as preformulation.

Preformulation commences when a newly synthesized drug shows sufficient pharmacologic promise in an animal model to warrant an evaluation in man. These studies should focus on the physiochemical properties of the new compound that could affect drug performance and the development of an efficacious dosage form. A thorough understanding of these properties may ultimately provide a rationale for formulation design or support the need for molecular modification. In the simplest case, these preformulation investigations may merely confirm that there are no significant barriers to product development.

Definition

• Preformulation is the prerequisite of formulation, for the development of safe and effective dosage forms for clinical use.
• Preformulation involves the application of biopharmaceutical principles to the physicochemical parameters of drug substances characterized with the goal of designing an optimum drug delivery system.
• A stage of development during which the physicochemical properties of a drug substance are characterized. Before beginning the formal pre-formulation programs the pre-formulation scientist must consider the following factors:

1. The number of drugs available.
2. The physicochemical properties of the drug are already known.
3. Therapeutic category and anticipated dose of the compound.

• During the early development of a new drug substance, the synthetic chemist, alone or in cooperation with specialists in other disciplines(including pre-formulation), may record some data that can be appropriately considered as pre-formulation data.

Correlation between Preformulation and Formulation

It is only on relatively few occasions that a drug as such may be directly administered to a patient. Usually, the medicament must be mixed with the appropriate stabilizers, preservatives, etc., and subjected to various processes to give a practical dosage form, in other words, the medicament must be formulated. Thus a dosage form must act as a vehicle for drug delivery. The information generated out of an exhaustive pre-formulation study certainly provides the necessary platform. The selection of correct excipients in the correct proportion is an important step in formulation development so as to product development.

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Steps in the Preformulation Process

Stability

• Solid State

1. Temperature
2. pH-Solubility Profile
3. Humidity
4. Light

• Solution

1. Solvent
2. pH
3. Light

Solid State Compatibility

• TLC Analysis
• DRS Analysis

Physico-chemical Properties

• Molecular weight
• Color
• Odor
• Particle size, Shape, and Crystallinity
• Melting Point
• Thermal Analysis Profile

1. DTA
2. DSC
3. TGA

• Hygroscopicity Potential
• Absorbance Spectra

1. UV
2. IR

• Solubility

1. Water and Other Solvents
2. pH-Solubility Profile
3. Salt Forms
4. Cosolvents
5. Complexation
6. Prodrug

• Effect of pH on
• UV Spectra
• Ionization Constant
• Optical Activity
• Polymorphism Potential
• Solvate Formation

Physico-mechanical Properties

• Bulk and Tapped Density
• Compressibility
• Photomicrograph

In-Vitro Availability Properties

• Dissolution of Drug Crystal Per se
• Dissolution of Pure Drug Pellet
• Dissolution Analysis of Pure Drug
• Rat Everted Gut Technique

Other Studies

• Plasma Protein Binding
• Effect of Compatible Excipients on Dissolution
• Kinetic Studies

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