11th February 2020 - Tablets: A General Formulation Overview
Tablets continue to be one of the most popular pharmaceutical dosage forms, as with the right tablet formulation you can achieve: ease of handling and administration for patients, stability convenient packing options, and well-established cost-effective manufacturing processes which produce consistent quality products.
However, there are also disadvantages which can include: poor bioavailability, instability within the gastrointestinal (GI) tract and the potential of causing irritant effects or harming the GI mucosa. Many of these can be mitigated against through successful tablet formulation development.
There are many different types of tablets and drug-release technology that can be applied to the formulation. In the previous article the types and versatility of tablets were covered, this week follows on this topic by covering the formulation strategies and manufacturing processes of tablets which are part of the development and manufacturing services available from Upperton.
As mentioned in the previous article, tablets consist of one or more API and a number of excipients that impart various functional attributes onto the tablet formulation and its performance both in during processing and following administration to the patient.
Types of common excipients include:
- Filler (or diluent) – ensures tablet is a reasonable handling size
- Matrix former – controls release of drug
- Disintegrant – ensures break down of tablet upon contact with a liquid
- Dissolution enhancer – speeds up rate of dissolution which is useful for poor solubility APIs
- Absorption enhancer – affects permeability of intestinal cell membranes
- Binder – aids adhesion between the tablet constituents and imparts mechanical strength
- Glidant – improves flowability of powder which ensures reproducible fills weights during manufacture
- Lubricant – ensures tablet formation and ejection within tablet press
- Flavours and taste masking agents – gives tablet a more pleasant taste
- Colourant – aids identification
Excipient selection is a key factor in the design of an effective dosage form that will reproducibly deliver its therapeutic effect and facilitate processing.
Initial formulation design should carefully consider the compatibility of the various excipients with the API and with each other. This is achieved by conducting an excipient compatibility study at accelerated stressed conditions typically over a number of weeks where an extensive range of excipients are screened.
Following the compatibility study, the formulator will select suitable excipient based on:
- Functional and processing requirements.
- Stability and solubility properties.
- Data from pre-formulation material characterisation studies (i.e. compactional simulation).
- Regulatory restrictions, certain excipients are approved or limited for particular applications.
- Commercial considerations (i.e. cost and marketing requirements).
The tablet manufacturing process is generally a combination of several individual unit operations; which aim to produce a uniformly blended powder that processes the necessary characteristic to be compressed into a tablet of fixed weight and hardness on a high speed tablet machine such as the KG Pharma Futorque tablet press used at Upperton.
Initially the API itself may need that application of an enabling technology as spray drying to convert it from a poorly soluble crystalline form to a more soluble amorphous form or micronisation to reduce the particle size and increase the surface area of the drug particles.
The API either in its original or modified form is then combined with some of the excipients typically using a Comill followed by a blending step. Control, design and monitoring of this blending step is critical to ensure that the powder blend is uniformly mixed and that the drug homogenously distributed through the excipients.
Depending on the characteristics of the blended powder compression into tablets can be achieved by three main processing categories:
Direct Compression – as a result of the inherent material properties the blended can be directly transferred to a tablet machine and compressed with no further processing required. The material properties of the API and excipients have sufficient flowability and compressibility to form a reproduce tablet of suitable strength and drug release profile. This is the most cost effective and simplest version of tablet compression but few materials possess the required properties to make it feasible and typically drug loading is low in these tablets. However, there are an increasing number of excipients available that have been specifically designed to aid direct compression.
Wet Granulation – in order to improve the processability of the powder blend and / or to modified its powder flow characteristics, its mechanical properties, drug homogeneity and its release performance additional excipients (e.g. binders and disintegrants) may be required. These are added to the API blend with a granulation fluid whilst applying a range of mixing techniques (e.g. low shear, high shear, fluid bed). The wet mas is then typically passed through a screen, dried, milled and blended before it is suitable for compressing on a tablet machine. The increased number of unit operations make this process more complex with many more critical process parameters to control and monitor while the requirements to wet the materials and then dry the materials often presenting stability challenges.
Dry Granulation – as with wet granulation this process is applied to improve the processing and performance characteristics of the powder blend to be compressed. In dry granulation additional excipient (e.g. binders and disintegrants) are again added to the blend and then using a roller compactor, high pressure rollers force the mixed powder blend together and result in adhesion of the particles into ribbons. These ribbons are then broken down into granules using a granulation screen / mill. Following a final blend, the material is then suitable for tablet compression. Again, there are a number of critical process parameters that must be controlled but the elimination of a wet granulation fluid and the requirement for drying make this more efficient process and more suitable for API that have stability issues associated with wet granulation.
Once the powder blend is in a suitable state for compression it is transferred to the tablet machine. The powder blend with the uniformly distributed API and suitable flow properties feeds into a die cavity and compressed to controlled weight and hardness between an upper and lower punch. The design of the punches can be used to make tablets of various shapes and sizes and to include attributes such as a break-line or to add an identification mark or dose strength onto the tablets during compression.
Tablet presses come in many sizes and with a range of capabilities, the speed of rotation and the number of stations dictating the potential output delivered from a few hundred per hour to over a million per hour. Careful control of the processing parameters such as compaction pressure and speed are required to ensure all tablets are produced to the same specifications.
Once manufactured the tablet core need to be subjected to further processing operations such de-dusting to remove any loss uncompacted powder on the tablet surface collected from the tablet press and metal checked to ensure that no metal fragments have been inadvertently picked from a damaged tablet machine or tablet punch and weight sorting to ensure all tablets deliver the correct dose
In most cases tablets are then film coated. Coating can be performed by a number of techniques such as fluid bed coating or pan coating in equipment such as the O Hara Labcoat MX as used at Upperton. In some instances, the coating is non-functional and is purely for handling, administration or aesthetic reasons. In other instances the coating may be required to control the release profile of the tablet such as enteric coating which ensures that tablet will not disintegrate in the stomach pH or for taste masking to ensure the patient is not put off taking the medicine by an unpleasant taste.
Overall the tablet process offers a vast array of options for the formulation scientist to ensure that the API is delivered to the patient in a form that is easy to administer and is off a consistent quality with the desired release profile.