Preformulation studies evolved in the 1950s and early 1960s. Preformulation testing or the study is the first step in developing finished dosage forms of a drug substance. The Preformulation study is defined as an investigation of the Physical or Chemical properties of a drug substance alone or in combination with the excipients. The main objective of this study is to generate information that is useful in developing stable and bioavailable dosage forms for the welfare of human beings.

Preformulation investigations are meticulously designed to provide a comprehensive understanding of drug substances, excipients, and packing materials. They yield crucial information about the physico-chemical, physico-mechanical, and biopharmaceutical properties of these components under various conditions, including different temperatures and humidity levels. This wealth of information, coupled with the preformulation study’s role in the discovery phase of a new chemical entity, underscores its pivotal position in assessing the ability and potency of a drug molecule.

Preformulation Parameters:

The Preformulation parameters are classified into four categories.

  1. Physical Parameters
  2. Chemical Parameters
  3. Solubility Analysis
  4. Stability Analysis

Physical Parameters

The Physical parameters are classified into Organoleptic Properties and Bulk properties.

I. Organoleptic Properties:

Any preformulation activity should begin with the description of a drug substance hence the colour, odour, and taste of a new drug comes under organoleptic properties.

II. Bulk Characteristics:

The bulk properties of the drug substances play a major role in formulating the finished dosage forms.

     a. Solid-state characteristics
     b. Flow properties
     c. Densities
     d. Compressibility
     e. Crystallinity & Polymorphism
     f. Hygroscopicity

a. Solid-state characteristics:Generally, powders are masses of solid particles or granules surrounded by air. The solid plus fluid combination significantly affects the drug’s bulk properties.

b. Flow properties: Flow properties of powders are critical for efficient tabletting operations. A good flow of powder blend will give efficient mixing of blend and achieve uniform tablet weight.

  • Angle of Repose: The maximum angle which is formed between the surface of the pile of powder and the horizontal surface is called the angle of repose.

Tan ϴ = h/r

h- height of heap of file
r- radius of the base of file

Angle of repose value is
< 25˚         – Excellent flow
25˚-30˚    – Good flow
30˚-40˚    – Moderate flow
>40˚          – Poor flow

c. Densities: The ratio of mass to volume is known as density.

  • Bulk density: This is obtained by measuring the volume of a known mass of the powder that passes through the screen.
  • Tapped density: It is obtained by mechanically tapping the measuring cylinder containing powder.
  • True density: It is the actual density of the solid material.
  • Granule density: This affects the tablet porosity, compressibility, disintegration, and dissolution of the drug.

     Carr’s Index: (Tapped density – Bulk density x 100) / Tapped density

     Hausner’s Ratio: Tapped density / Bulk density

d. Compressibility:
Compressibility refers to the ability of a powder to decrease in volume under pressure, which is crucial for tablet formation. It determines how well a powder can be compacted into a cohesive solid form. Factors affecting compressibility include particle size, shape, distribution, and moisture content. Compressibility is often measured by compressibility index (Carr’s Index) and Hausner’s Ratio. Higher compressibility leads to better tablet formation with desired hardness and minimal friability.

e. Crystallinity and Polymorphism:These are the two parameters that denote the physical state of the drug. Crystallinity is the unique arrangement of atoms in a lattice or a crystal. The existence of a drug substance in more than one crystal form is known as Polymorphism.

f. Hygroscopicity: Generally, many compounds and salts are sensitive to moisture which means they can interact with the moisture present in the atmosphere and they can retain the water by bulk or by surface absorption is called hygroscopicity.

Chemical Parameters:

The following are the chemical parameters that play a crucial role in the degradation of drug substances.

  1. Hydrolysis: Taking the water or moisture from the atmosphere results in the generation of amide group impurity in the formulation, resulting in the drug degradation by hydrolysis.
  2. Oxidation: Taking the oxygen from the atmosphere results in the discoloration of a few actives results in drug degradation and generates peroxide impurities.
  3. Reduction: Here the drug degradation happens with the generation of Nitro or Azo impurities in the drug substance this process is called reduction.

Solubility Analysis:   

This is the most important physico-chemical property of the drug which in turn called as solubility of the drug substance. The amount of drug that dissolves in a given amount of solvent is called solubility and the solubility of the drug vary at different pH inside the body. Based on the solubility and permeability we have four classes of drugs also known as BCS classification.

BCS Class I – High Soluble and High Permeable

BCS Class II- Low soluble and High Permeable

BCS Class III- High soluble and Low Permeable

BCS Class IV- Low soluble and Low Permeable

Stability Analysis:

The flow properties of the final lubricated blend plays a predominant role during the manufacturing of pharmaceutical dosage forms like tablets and capsules. For example, if the bulk density (BD) of the lubricated blend is above 0.55 g/ml during tablet compression, the tablet will move freely from the die wall to the turret. However, if the bulk density (BD) is 0.30 g/ml, it becomes difficult for the tablet to exit the die wall, leading to issues such as chipping, capping, lamination, and sticking.

Conducting thorough preformulation studies during the initial stages of developing a pharmaceutical dosage form can resolve concerns related to both the machines and materials involved in product manufacturing. This is why the US FDA introduced the Quality by Design (QbD) concept in 2006. Since 2013, the FDA has mandated the inclusion of a QbD report for product filings in the US market. One of the most crucial pieces of information to be included in this QbD report is the preformulation parameters of the dosage form.

By performing thorough preformulation studies before developing a pharmaceutical dosage form, we can resolve concerns related to both machines and materials involved in product manufacturing from the initial stages. This is why, in 2006, the US FDA introduced the Quality by Design (QbD) concept. Since 2013, the FDA has required a QbD report for products filing in the US market. One of the most important data points that need to be captured in this QbD report is the preformulation parameters of the dosage form.

Preformulation studies are an essential initial step in the development of pharmaceutical dosage forms, providing vital information on the physical, chemical, and biopharmaceutical properties of drug substances. By thoroughly investigating parameters such as solid-state characteristics, flow properties, densities, compressibility, crystallinity, polymorphism, and hygroscopicity, scientists can predict and enhance the stability, bioavailability, and manufacturability of drug products. Understanding these properties helps in designing dosage forms that meet regulatory standards and ensure therapeutic efficacy. The incorporation of solubility and stability analysis further refines the formulation process, leading to the development of robust and reliable pharmaceutical products.

anish pharma, a process solutions expert for the pharmaceutical industry for the last three decades, specializes in granulation and pelletisation and offers advanced expertise to optimize and enhance pharmaceutical manufacturing processes.