口服固体制剂开发和生产中需要优化的关键参数

Oral solid-dosage forms (typically, tablets and capsules) are manufactured using conventional manufacturing processes such as direct blending or granulation techniqueswet granulation, dry granulation/roller compaction, or fluid bed granulation followed by fluid bed drying, milling, compression, and coating. It is important to understand the critical processing parameters (CPPs) that impact critical quality attributes(CQA). The CQAs that impact the final outcome (i.e., the therapeutic efficacy of the drug product) usually are parameters such as in-vitro dissolution and drug product stability. In-vitro dissolution of the drug can influence the rate and extent of drug absorption. Drug substance properties such as particle size, morphology, dosage strength, and drug loading have a big impact on the blending process and can influence the homogeneity of the drug substance in the blend. Blending is a critical process that needs to be optimized and is considered a CPP that can impact the potency of the finished product. Similarly, each of the granulation techniques has a processing step that could cause variability and has the potential of impacting the CQAs. Key parameters that need to be optimized (see Table I) will depend on the API properties, its stability, dose, drug loading, and other factors.

口服固体制剂（例如片剂和胶囊剂）都可以采用传统的制造工艺如直接混合造粒技术、湿法造粒技术、干法造粒技术、流化床造粒/干燥技术，包括粉碎、压片、包衣等工序。理解影响关键质量属性（CQA）的关键工艺参数（CPPS）很重要。CQA是那些影响药物最终结果（如疗效）的因素，如体外溶出和药物的稳定性。药物的体外溶出可以影响药物吸收的速度和程度。药物的性质如粒径大小、形态、剂量和载药量对混合过程有很大影响，并会影响药物的混合均匀性。混合是一个需要进行优化的关键，它可以影响成品的含量。每一种制粒技术都包括一个可能引起变异和对CQAs有潜在影响的工序。表1中列出了需要优化的关键参数，这取决于原料药（API）的性质、稳定性、剂量、载药量及其他因素。

A typical process optimization methodology includes a systematic identification of CQAs, CPPs, and a risk assessment to identify the critical selection of key parameters. A plan can then be drawn up, using a statistical design of experiments (DOE), which can be a full- or partial-factorial design, based on the availability of API and the number of runs that can be manufactured. The DOE experiments involve running parameters at high, medium, and low values, as well as running a defined number of control runs at target parameters. By analyzing the data from the DOE runs, a design space can be identified. Knowledge of the design space enables a control strategy to be defined for the manufacture of the product.

A similar approach is taken for formulation optimization, in which critical functional formulation excipients are evaluated with high, medium, and low levels, and the impact of these variables is studied on output parameters of that functionality (e.g., disintegrant levels studies can be done with the rate of disintegration of tablets as the output).

A systematic DOE to optimize the formulation composition in an oralsolid-dosage form is important for two main purposes:

（1）To ensure the optimum level of a functional excipient in the formulation. In an immediate-release tablet formulation, excipient levels of binder, disintegrant, and lubricant can be varied and the functionality challenged. A partial or full factorial DOE can evaluate multiple excipients at different levels of the excipient. For an extended-release tablet formulation based on a hydrophilicgel matrix, polymer levels will affect the release rate of the drug from the tablet. Hence, the level of polymer is selected based on the specifications or the target release profile.

（2）To optimize the drug load in a formulation to reduce the pill burden, especially for a large dose drug product. Many oral solid-dose products need tobe formulated in doses above 100 mg per unit tablet or capsule. There are quite a few new chemical entities that need a much higher dose up to a 500 or 750 mg per unit dose. Fixed-dose combination therapies are becoming more popular, due to synergistic therapeutic effects and as a lifecycle management strategy. The number of actives and the dose per unit tablet are increasing. Thus, there is a need to formulate such products in a way that the tablet size is reasonable to swallow, especially for geriatric patients. It is important, therefore, to optimize the formulation so that the drug load in a tablet is as high aspossible, which also means that there is little room for inert excipients. Selecting the right functional excipient in the right quantity thus becomes more crucial.

Products with multiple doses use a “dose weight proportional” strategy-using the same formulation composition (drug to excipient ratio) and compressing the larger dose into a larger tablet size. This strategy has the benefit of avoiding a separate stability study as the drug to excipient ratiois the same; however, the disadvantage is that the higher dose becomes a large tablet, which may present “patient compliance” issues because of difficulty in swallowing. The limited time available for developing clinical trial formulations often makes optimization of drug load and tablet size a low priority.

During this stage, however, it is important that the choice ofexcipients, level of excipients, the drug load, and reduction of pill size and burden are optimized. Polypharmacy is a huge problem, and patients would benefit greatly if better drug products that are easier to swallow can be developed. Optimizing the formulation at the right stage in the development program by increasing the drug load per unit tablet or capsule, thereby, reducing the pill burden, would be beneficial.

文章来源：Pharmaceutical Technology Vol. 41, No. 4 Pages: 18

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