Excipients compatibility, drug products

Formulation Development. The formulation of the new drug product will be designed in conjunction with medical and marketing input. Excipients to be used will be tested for chemical and physical compatibility with the drug substance. The preliminary formulation design will be optimized at this stage. 

Formulation profile, which consists of physical and chemical characteristics required for the products, drug-excipient compatibility studies, and the effect of formulation on in vitro dissolution... 

In addition, simple binary studies with key excipients should be done to establish physical and chemical compatibility between the API and the selected excipient. These studies need not be elaborate, but will provide useful information to the formulator during the critical drug product development stage. 

Some excipients contain a certain amount of amorphous form such as spray-dried lactose,27 and others are hygroscopic, such as microcrystalline cellulose.28 These excipients will adsorb water, which causes a change in the micro-environment of the formulation. If the drug substance is moisture-sensitive, degradation may occur quickly. Therefore, consider both drug-excipient compatibility and excipient impurity profile in selecting excipients for low-dose drug products. 

In the following excipient compatibility example, drug substance was put on accelerated stability with different binary ratios of varied excipients and stored at 2 weeks and 4 weeks at dry and humid conditions, 50°C (dry) and 50°C/75% relative humidity, respectively (Figure 15-7). With most of the excipients under dry conditions, it was observed that the level of increase of degradation products in the binary mixtures was less than 0.2%. However, under 50°C/75%RH conditions, most of the excipients showed increasing degrada-... 

For this reason, a drug product that is to be used multiple times (multidose) must contain a preservative to prevent bacterial growth. A list of preservatives that have been used in pharmaceutical formulations is shown in Table 2. However, most of these are not usually compatible with protein formulations. Some, such as the parabens, are not active in the presence of nonionic surfactants—excipients that are typically required in protein formulations.Others may not be acceptable for a particular route of administration. Benzalkonium chloride, a commonly used preservative in topical formulations, causes ototoxicity when applied to the ear. As with buffering species, the list of preservatives available to the formulation scientist quickly narrows to just a few compounds including benzyl alcohol, phenol, w-cresol, and benzethonium chloride. A benzyl alcohol-containing formulation of epoetin alfa has been shown to be stable, even when dispensed in plastic syringes. ... 

Normally, a pharmaceutical development report is written in the United States, which should be available at the time of Pre-Approval Inspection (PAI). The development report contains the choice of excipients, their purpose and levels in the drug product, compatibility with other excipients, drug or package system, and how they may influence the stability and efficacy of the finished producf. 

Conditions for the LAL reaction with endotoxin require pH neutrality and optimum levels of sodium and divalent cations. A uniform temperature of 37°C optimizes the rate of reaction. Most therapeutic drug products require dilution with LAL reagent water (LRW) before testing to avoid interference, which is recognized by improper recovery of the positive product control (PPC). Inhibition is a failure to recover the PPC, whereas enhancement is high recovery of the PPC. Cooper has described ways to identify the concentration of a substance, which is chemically compatible with the BET, and to validate the BET with drug products and excipients. 

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