The development of an efficient dosage form usually starts with preformulation studies. These studies are designed to investigate and deliver all necessary data useful to the formulator in developing an optimum drug delivery system that can be mass produced.  In this post, the discussion is focused on bulk characterization of candidate drug molecules in a drug discovery setting.

Bulk characterization of drug molecules involves the characterization of various solid-state properties that could change during process development. Variability of bulk characteristics, such as particle size, shape and surface area, powder flow properties, bulk and tapped density etc., significantly dictate many subsequent events and approaches in drug development processes. Bulk characterization testing includes:

1. Particle size and surface area

Powders are likely the least predictable of all materials with respect to flowability. This is because there are a whole lot of factors that can change their flow properties. In tablet formulation, particle size distribution and shape influence mixing efficiency and flow properties of powders and granules. In addition to the effects of particle size distribution and shapes on various physicochemical properties of a drug substance, the biopharmaceutical behaviors of drug substances are equally affected. For instance, the bioavailability of a poorly soluble drug showing a dissolution rate limiting step in the absorption process can be enhanced when administered in a finely divided state rather as a coarse material.

2. Powder flow properties

Flow properties of powders can be influenced by changes in particle size, shape and density as well as electrostatic charges and adsorbed moisture. Flow properties depend on frictional force and force of cohesion between one powder particle and another. Thus, an in-depth knowledge of the flow properties of powders is essential for an efficient mixing and tableting process. Also, there is need to establish as early as possible how the flow properties of a powder may affect formulation and efficacy especially when the expected dose of the drug is large. Powder flow properties are characterized by determining the angle of repose, compressibility index also called Carr’s index, Hausner ratio etc.

3. Density

Bulk and tapped density are measures of densification pattern and packing, or arrangement of any powder. These two parameters play a role in packing and particle arrangement of powders, the volume occupied by a given powder bed and the ease with which the powder will flow under a given condition. It is important to understand these parameters as they are very essential in forming some ideas to the size of the final dosage form.

4. Compressibility

Compressibility is a measure of the relative volume change of powders, that is, its ability to decrease in volume or deform under pressure. This property is useful in selecting appropriate formulation ingredients.

5. Crystallinity

This refers to the unique arrangement of constituent atom or molecules of solids in a regular, periodic pattern. Most candidate drug molecules exist as solid with very few existing as liquids and even less in gaseous form. When dissolved in different solvent under different processing conditions, crystalline substances losses its crystal nature and its polymorphic state modified in addition to change in character or composition of the recrystallized particles. The degree of crystallinity of drug substances has marked effect on its hardness, density, transparency and diffusion. This influences both the choice of the delivery system and activity as determined by the rate of delivery.

6. Polymorphism

This is the ability of a solid material to crystallize forming at least two different crystalline species with distinct internal lattice. These different molecular arrangements disappear in liquid and vapour states. Polymorphs differ from one another with respect to their physical properties (e.g., solubility, melting point, optical and electrical properties, hardness, compression properties, density etc.,) and of great concern is their stability and solubility. The need to identify the most stable polymorph at room temperature can never be overemphasized.

7. Hygroscopicity

Many drug substances usually absorb or lose moisture from the atmosphere to achieve equilibrium with the water in the atmosphere. The amount of moisture absorbed or lost by a given quantity of a drug substance can vary significantly and continually depending on the relative humidity and air temperature. This cyclic changes lead to constant variations in the moisture content of unprotected drug substances and excipients and in turn affect the stability, flow properties, compatibility etc., of drug substances.

References

• Aulton M. E and Taylor M. (2013). Aulton’s Pharmaceutics: The Design and Manufacture of Medicines. Amsterdam, Netherlands: Churchill Livingstone Elsevier.
• Chaurasia G. (2016). A Review on Pharmaceutical Preformulation Studies in Formulation and Development of New Drug Molecules. International Journal of Pharmaceutical Science and research, 7(6): 2313-2320.
• Gibson, M. (2004). Pharmaceutical Preformulation and Formulation: A Practical Guide from candidate Drug Selection to Commercial Dosage Form. Florida: CRC Press LLC.
• Kulkarni, S., Sharma, S. and Agrawal, A. (2015). Preformulation – A Foundation For Formulation Development. International Journal of Pharmaceutical, Chemical And Biological Sciences, 5(2): 403-406.
• Kumar, P., Vaishnavi, G., Divya, K. and Lakshmi, U. (2015). An Overview on Preformulation Studies. Indo American Journal of Pharmaceutical Science, 2(10): 1399-1407.
• Leo, A., Hansch C., and Elkins D. (1971). Partition Coefficients and Their Uses. Chemical Reviews, 71(6): 525-616.
• Onyishi, I. V. (2015). Lecture on Personal Collection of Onyishi, University of Nigeria, Nsukka, Enugu State.