Chapter 16 Pharmaceutical development

Introduction

Active pharmaceutical ingredients (API) in pharmaceutical products must be formulated to dosage forms suitable for handling, distribution and adminstration to patients. Common dosage forms are tablets and capsules, liquids for injection, patches for transdermal administration and semisolids for dermal application. Development and documentation of dosage forms is complex involving several stages and areas of expertise. In the preformulation phase the chemical and physicochemical properties of the drug substance are characterized. This information serves together with information about the disease, intended doses and preferred route of administration as the starting point for the formulation development. Stability of the drug substance is a cornerstone in the preformulation phase. Analytical pharmaceutical chemistry is crucial for successful formulation development. Impurities and degradation products must be identified and quantified. Uniformity of content in unit dosage forms is vital to assure that the patient is treated with correct doses.

This chapter describes the main steps involved in pharmaceutical development and is illustrated with examples of the most common formulations, tablets and capsules, since development of these dosage forms contains most of the steps involved in formulation development per se. Development of solutions for injection/infusion or other sterile dosage forms are not specifically discussed in this chapter.

Preformulation studies

As a starting point to developing dosage forms, various physical and chemical properties of the drug substance need to be documented. These investigations are termed preformulation studies. Most synthetic drugs are either weak bases (~75%) or weak acids (~20%), and will generally need to be formulated as salts. Salts of a range of acceptable conjugate acids or bases therefore need to be prepared and tested. Intravenous formulations of relatively insoluble compounds may need to include non-aqueous solvents or emulsifying agents, and the compatibility of the test substance with these additives, as well as with the commonly used excipients that are included in tablets or capsules, will need to be assessed.

The main components of preformulation studies are:

• Development of a suitable spectroscopic assay method for determining concentration and purity

• Determination of solubility and dissolution rates of parent compound and salts in water and other solvents

• Chemical stability of parent compound and salts in solution and solid state

• Determination of pK_a and pH dependence of solubility and chemical stability

• Determination of lipophilicity (i.e. oil:water partition coefficient, expressed as K_d)

• Determination of particle morphology, melting point and suitability for milling

• Characterizations of importance for the dosage forms of choice, e.g. bulk density, powder flow, angle of repose and compression properties.

Theoretical treatments of these molecular properties, and laboratory methods for measuring them, which are beyond the scope of this book, are described in textbooks such as Burger and Abraham (2003), Aulton (2007) and Allen (2008). Here we consider some issues that commonly arise in drug development.

Solubility and dissolution rate

The question of solubility, already emphasized in Chapters 9 and 10, is particularly important in relation to the development of pharmaceutical formulation. It is measured by standard laboratory procedures and involves determining the concentration of the compound in solution after equilibration – usually after several hours of stirring – with the pure solid. In general, compounds whose aqueous solubility exceeds 10 mg/mL present no problems with formulation (Kaplan, 1972). Compounds with lower solubility are likely to require conversion to salts, or the addition of non-aqueous solvents, in order to achieve satisfactory oral absorption. Because the extreme pH values needed to induce ionization of very weak acids or bases are likely to cause tissue damage, the inclusion of a miscible solvent of relatively low polarity, such as 20% propylene glycol or some other biocompatible solubilizing agent (see below), will often be required for preparing injectable formulations. Complications may arise with oral formulations if the solubility is highly dependent on pH, because of the large pH difference between the stomach and the small intestine. Gastric pH can range from near neutrality in the absence of any food stimulus to acid secretion, to pH 1–2, whereas the intestinal pH is around 8. Basic substances that dissolve readily in the stomach can therefore precipitate in the intestine and fail to be absorbed. Compounds that can exist in more than one crystal form can also show complex behaviours. The different lattice energies of molecules in the different crystal forms mean that the intrinsic solubility of the compound is also different. Different crystal forms may correspond to different hydration states of the compound, so that a solution prepared from the unhydrated solid may gradually precipitate as hydrated crystals. Selecting the best salt form to avoid complications of this sort is an important aspect of preformulation studies.

Compounds that have low intrinsic solubility in aqueous media can often be brought into solution by the addition of a water-miscible solubilizing agent, such as polysorbates, ethanol or polyethylene glycol (PEG). Preformulation studies may, therefore, include the investigation of various solubilizing agents, such as methylcellulose or cyclodextrin, which are known to be relatively free of adverse effects in man.

As well as intrinsic solubility, dissolution rate is important in determining the rate of absorption of an oral drug. The process of dissolution involves two steps: (a) the transfer of molecules from the solid to the immediately adjacent layer of fluid, known as the boundary layer; and (b) escape from the boundary layer into the main reservoir of fluid, which is known as the bulk phase and is assumed to be well stirred so that its concentration is uniform. Step (a) is invariably much faster than step (b), so the boundary layer quickly reaches saturation. The overall rate of dissolution is limited by step (b), and depends on the intrinsic solubility of the compound, the diffusion coefficient of the solute, the surface area of the boundary layer, and the geometry of the path leading from the boundary layer to the bulk phase.

In practice, dissolution rates depend mainly on:

• Intrinsic solubility (since this determines the boundary layer concentration)

• Molecular weight (which determines diffusion coefficient)

• Particle size and dispersion of the solute (which determine the surface area of the boundary layer and the length of the diffusion path).

In pharmaceutical development, dissolution rates are often manipulated intentionally by including different polymers, such as methylcellulose into tablets or capsules, to produce ‘slow-release’ formulations of drugs such as diclofenac, allowing once-daily dosage despite the drug’s short plasma half-life.

Stability

For routine use, a drug product is expected to have a shelf-life, representing less than 5% decomposition and no significant physical change under normal storage conditions, of at least 3 years.

During the preformulation studies stability tests are often carried out for 1–4 weeks. The chemical stability of the solid is measured at temperatures ranging from 4 to 75°C, and moisture uptake at different relative humidities is also assessed.

Measurements of stability in solution at pH values ranging from 1 to 11 at room temperature and at 37°C will be performed, including formulations with solubilizing agents where appropriate. Sensitivity to UV and visible light, and to exposure to oxygen, is also measured.

The rate of degradation in short-term studies under these harsh conditions is used to give a preliminary estimate of the likely rate of degradation under normal storage conditions. Sensitivity to low pH means that degradation is likely to occur in the stomach, requiring measures to prevent release of the compound until it reaches the intestine.

These preformulation stability tests serve mainly to warn that further development of the compound may be difficult or even impossible. Definitive tests of the long-term (3 years or more) stability of the formulated preparation will be required at a later stage of development for regulatory purposes.

Particle size and morphology

Ideally, for incorporation into a tablet or capsule the drug substance needs to exist in small, uniformly sized particles, forming a smoothly flowing powder which can be uniformly blended with the excipient material. Rarely, the compound will emerge from the chemistry laboratory as non-hygroscopic crystals, and the melting point will be sufficiently high that it can be reduced to a uniform fine powder by mechanical milling. More often it will take the form of an amorphous, somewhat waxy solid, and additional work will be needed later in development to produce it in a form suitable for incorporation into tablets or capsules.

Preformulation studies are designed to reveal how far the available material falls short of this ideal. Various laboratory methods are available for analysing particle size and morphology, but in the preformulation stage simple microscopic observation is the usual method.

Particles larger than a few micrometres, particularly if the particle size is very variable, are difficult to handle and mix uniformly. Hygroscopic materials and polymorphic crystal forms are a disadvantage, as already mentioned. These issues are unlikely to matter greatly in the early stages of development, as Phase I studies can usually be carried out with liquid formulations if necessary, but can be a major hurdle later, so the main aim of the preformulation studies is to give a warning of likely problems to come.

Routes of administration and dosage forms

With the knowledge of the characteristics of the drug substance from preformulation studies, the administration route has to be selected and the substance to be included into a dosage form which is effective and convenient for the patient. The preferred dosage form for therapeutic agents is almost always an oral tablet or capsule, either taken as needed to control symptoms, or taken regularly once or several times a day. However, there are many alternatives, and Table 16.1 lists some of the main ones. An important consideration is whether it is desirable to achieve systemic exposure (i.e. distribution of the drug to all organs via the bloodstream) or selective local exposure (e.g. to the lungs, skin or rectum) by applying the drug topically. In most cases systemic exposure will be required, and an oral capsule or tablet will be the desired final dosage form. Even so, an intravenous formulation will normally be required for use in safety pharmacology, toxicology and pharmacokinetic studies in man.

Table 16.1 The main routes of administration and dosage forms

The main routes of administration for drugs acting systemically, apart from oral and injectable formulations, are transdermal, intranasal and oromucosal. Rectal, vaginal and pulmonary routes are also used in some cases, though these are used mainly for drugs that act locally.

Transdermal administration of drugs formulated as small adhesive skin patches has considerable market appeal, even though such preparations are much more expensive than conventional formulations. To be administered in this way, drugs must be highly potent, lipid soluble and of low molecular weight. Examples of commercially available patch formulations include nitroglycerin, scopolamine, fentanyl, nicotine, testosterone, estradiol and ketoprofen, and several others in development. The main limitation is the low permeability of the skin to most drugs and the small area covered, which mean that dosage is limited to a few milligrams per day, so only very potent drugs can be given systemically via this route of administration. Variations in skin thickness affect the rate of penetration, and the occurrence of local skin reactions is also a problem with some drugs. Various penetration enhancers, mainly surfactant compounds of the sort discussed above, are used to improve transdermal absorption. The transfer rate can be greatly enhanced by applying a small and painless electric current (about 0.5 mA/cm²), and this is effective in achieving transfer of peptides (e.g. calcitonin) and even insulin through the skin. It also offers promise as a route of administration of oligonucleotides in gene therapy applications (see Chapter 12). These procedures are used for administration of nucleotides and in gene therapy and are being used experimentally in the clinic, but are not yet available as commercial products for routine clinical use. Ultrasonic irradiation is also under investigation as a means of facilitating transdermal delivery. These procedures would also allow the administration to be controlled according to need. Intranasal drug administration (Illium, 2002, 2003) is another route that has been used successfully for a few drugs. The nasal epithelium is much more permeable than skin and allows the transfer of peptide drugs as well as low-molecular-weight substances. Commercially available preparations have been developed for peptide hormones, such as vasopressin analogues, calcitonin, buserelin and others, as well as for conventional drugs such as triptans, opioids, etc. The main disadvantages are that substances are quickly cleared from the nasal epithelium by ciliary action, as well as being metabolized, and the epithelial permeability is not sufficient to allow most proteins to be given in this way. Ciliary clearance can be reduced by the use of gel formulations, and surfactant permeability enhancers can be used to improve the penetration of larger molecules. The possibility of administering insulin, growth factors or vaccines by this route is the subject of active research efforts. Some studies have suggested (see Illium, 2003) that substances absorbed through the nasal epithelium reach the brain more rapidly than if they are given intravenously, possibly bypassing the blood–brain barrier by reaching the CNS directly via the nerves to the olfactory bulb.

Oromucosal delivery (Madhav et al., 2009) and especially utilizing the buccal and sublingual mucosa as the absorption site is a drug delivery route which promotes rapid absorption and almost immediate pharmacological effect. The sublingual mucosa, especially, is highly vascularized and this route bypasses the gastrointestinal tract and, thus, the first-pass metabolism. However, not all drugs can be efficiently absorbed through the oral mucosa because of physicochemical properties or enzymatic breakdown of the drug and the amount of drug that could be absorbed is limited to a few milligrams. The drug has to be soluble, stable and able to easily permeate the mucosal barrier at the administration site. Also some formulation aspects have to be taken into consideration, using a tablet formulation for a rapid onset of effect a prerequisite is a fast disintegration and dissolution in the oral cavity resulting in an optimal exposure of active substance to the small volume of dissolving fluids. Swallowing of the drug could be a potential problem, but can be minimized by using technologies using mucoadhesive components (Bredenberg et al., 2003; Brown and Hamed, 2007). An optimized formulation and using this administration route has the potential for very fast absorption (Kroboth et al., 1995) and obtaining peak blood levels within 10 to 15 minutes. It is thereby potentially a more comfortable and convenient alternative to the intravenous route of administration.