Essentials of Pharmaceutical Preformulation

Simon Gaisford, Mark Saunders

• Publisher: Wiley-Blackwell
• Year: 2012
• ISBN:
  9781118423240
• Edition: 1
• Topic: Biological Sciences
• Subtopic: Biotechnology
• Index: Biological Sciences

Essentials of Pharmaceutical Preformulation is a study guide which describes the basic principles of pharmaceutical physicochemical characterisation. Successful preformulation requires knowledge of fundamental molecular concepts (solubility, ionisation, partitioning, hygroscopicity and stability) and macroscopic properties (physical form, such as the crystalline and amorphous states, hydrates, solvates and co-crystals and powder properties), familiarity with the techniques used to measure them and appreciation of their effect on product performance, recognising that often there is a position of compromise to be reached between product stability and bioavailability.

This text introduces the basic concepts and discusses their wider implication for pharmaceutical development, with reference to many case examples of current drugs and drug products. Special attention is given to the principles and best-practice of the analytical techniques that underpin preformulation (UV spectrophotometry, TLC, DSC, XRPD and HPLC). The material is presented in the typical order that would be followed when developing a medicine and maps onto the indicative pharmacy syllabus of the Royal Pharmaceutical Society of Great Britain

Undergraduate-level pharmacy students and R&D / analytical scientists working in the pharmaceutical sector (with or without a pharmaceutical background) will find this text easy to follow with relevant pharmaceutical examples.

• Essential study guide for pharmacy and pharmaceutical science students
• Covers the pharmaceutical preformulation components of the Royal Pharmaceutical Society of Great Britain's indicative syllabus
• Easy to follow text highlighted with relevant pharmaceutical examples
• Self-assessment assignments in a variety of formats
• Written by authors with both academic and industrial experience
• Companion website with further information to maximise learning

1

Basic Principles of Preformulation Studies

1.1 Introduction

The worldwide market for pharmaceutical sales is large and has grown consistently year-on-year for much of the past decade (Table 1.1). The advent of computer-based drug design programmes, combinatorial chemistry techniques and compound libraries populated with molecules synthesised over many decades of research and development means there is a vast array of compounds with the potential to become drug substances. However, drug substances are not administered to patients as pure compounds; they are formulated into drug products. The selection of a compound, its development into a drug substance and, ultimately, drug product is a hugely time-consuming and expensive process, which is ultimately destined for failure in the majority of cases. As a rough guide, only 1 out of every 5–10 000 promising compounds will be successfully developed into a marketed drug product and the costs involved have been estimated at ca. $1.8 billion (Paul et al., 2010).

Table 1.1 Total market sales in the pharmaceutical sector from 2003 to 2010 (data from IMS Health).

While it is tempting to assume that all drug products are financial blockbusters, approximately 70% never generate sufficient sales to recoup their development costs. Table 1.2 shows the top 20 medicines by sales worldwide (and the percentage of revenue they generate for their respective companies). It is apparent that a significant percentage of income is generated from these blockbuster products, and the financial health and prospects of the originator company are largely dependent upon the extent of patent protection (allowing market exclusivity) and new drug products in the development pipeline.

Table 1.2 Top ten drugs by sales worldwide in 2010 (data from IMS Health).

These numbers imply that development of a drug product in the right therapeutic area can result in significant income, but the costs involved in reaching market are such that only a few potential drug substances can be considered for development. How best to select a compound for development from the myriad of chemical structures that may be available? It is tempting to think that the decision reduces to efficacy against a biological target alone, but in practice physicochemical properties affect how a substance will process, its stability and interaction with excipients, how it will transfer to solution and, ultimately, define its bioavailability. The compound showing greatest efficacy may not ultimately be selected if another compound has a better set of physicochemical properties that make it easier to formulate and/or manufacture. It follows that characterising the physicochemical properties of drug substances early in the development process will provide the fundamental knowledge base upon which candidate selection, and in the limit dosage form design, can be made, reducing development time and cost. This is the concept of preformulation.

1.2 Assay design

In the early stages of preformulation the need rapidly to determine bioavailability, dose and toxicity data predominate and hence the first formulations of a drug substance are usually for intravenous injection. The first task facing any formulator is thus to prepare a suitable formulation for injection – most often this requires only knowledge of solubility and the development of a suitable assay. It is extremely important to note here that no development work can proceed until there is a suitable assay in place for the drug substance. This is because experimentation requires measurement.

1.2.1 Assay development

Assays greatly assist quantitative determination of physicochemical parameters. Since each assay will in general be unique to each drug substance (or, more correctly, analyte) development of assays may be time-consuming in cases where many drug substances are being screened. The first assays developed should ideally require minimum amounts of sample, allow determination of multiple parameters and be applicable to a range of compounds. For instance, a saturated solution prepared to determine aqueous solubility may subsequently be used to determine partition coefficient, by addition of n-octanol.

Note at this stage that determination of approximate values is acceptable in order to make a go/no go decision in respect of a particular candidate and so assays do not need to be as rigorously validated as they do later in formulation development. Table 1.3 lists a range of molecular properties to be measured during preformulation, in chronological order, and the assays that may be used to quantify them. These properties are a function of molecular structure. Once known, further macroscopic (or bulk) properties of the drug candidate can be measured (Table 1.4). These properties result from intermolecular interactions. Note also that determination of chemical structure does not appear, as it is assumed that the chemists preparing the candidate molecules would provide this information. Note also that solubility will be dependent upon physical form (polymorph, pseudopolymorph or amorphous).

Table 1.3 Molecular sample properties and the assays used to determine them.

Property	Assay	Requirement of sample
Solubilitya Aqueous Nonaqueous	UV	Chromophore
pKa	UV or potentiometric titration	Acid or basic group
Po, w/log P	UV TLC HPLC	Chromophore
Hygroscopicity	DVS TGA	No particular requirement
Stability Hydrolysis Photolysis Oxidation	HPL...