Key parameters to be optimized in the development and manufacturing of oral solid-dosage forms

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.

Table I: Process and critical process parameters that require optimization.

Process

Critical process parameters

Blending

Blending time

Number of revolutions of the blender

High shear wet granulation

Kneading time

Impeller and chopper speed

Binder addition time

Fluid bed drying

Inlet air temperature

Fluidization air volume

Dew point

Product temperature

Roller compaction

Roll gap

Roll width

Roll pressure

Screen size

Fluid bed granulation

Spray volume

Spray rate

Inlet air temperature

Milling

Screen size

Compression

Compression force

Compression speed

Dwell time

Coating

Spray rate

Inlet air temperature

Encapsulation

Speed of encapsulation

Tamping pressure

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 oral solid-dosage form is important for two main purposes:

• 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 hydrophilic gel 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.

• 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 to be 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 as possible, 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 ratio is 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 of excipients, 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.

About the Author

Anil Kane is executive director, Global Head of Formulation Sciences, Pharmaceutical Development Services at Patheon.

Article Details

Pharmaceutical Technology
Vol. 41, No. 4
Pages: 18

Citation

When referring to this article, please cite it as A. Kane, “Key parameters to be optimized in the development and manufacturing of oral solid-dosage forms” sidebar to “Designing Optimized Formulations," Pharmaceutical Technology 41 (4) 2017.