Study carried out using Gamlen Tablet Press
Tablet formulation and reformulation suffers from the issue that prior design is difficult based on present knowledge. A critical attribute of a formulation is not routinely tested – namely its compressibility. In this paper we present a systematic approach to tablet formulation development using a Gamlen Tablet Press capable of providing a compressibility assessment on milligram quantities of material. We evaluated a number of direct compression excipients as possible substitutes for an existing wet granulated formulation, maintaining as closely as possible the original qualitative formula. The change of the wet granulation manufacturing step to a direct compression process would not only save the manufacturer time and cost but also provide a simple regulatory change route if the excipients remain the same.
Materials and methods
We investigated the compressibility of various formulations of a well-known blood pressure medicine, comparing the existing wet granulated formulation with various substitutions of direct compression excipients.
Tablets were formed using the Gamlen Tablet Press GTP1 (Nottingham UK) at various compaction forces-100, 200, 300 and 400kg. 100mg of each material was compressed to form a 6mm round faced tablet. Data was collected on the compression profile, weight and thickness of the tablet formed. Some tablets were then subsequently crushed on the same instrument and the fracture profile recorded as well as peak fracture load. From the tablet dimension and force applied the tensile strength of the tablet is calculated according to the solution for flat faced round tablets (Newton and Fell J Pharm Sci 59; 688-691,1970);
σ = tensile strength (MPa), P = fracture load (N), D= diameter (mm), t= tablet thickness (mm)
This was repeated for all formulations and a profile of the formulations compressibility and tensile strength of subsequent tablets built up. Dissolution testing of the various intact tablets was then carried out to determine the effect of excipient substitution on bioavailability.
Results and discussion
Compressibility assessments showed clear differences between the formulations. In particular we see how extra microcrystalline cellulose and agglomerated lactose 80 have a major effect on tensile strength of the tablet compared to the existing wet granulated material, whilst other formulations are worse.
The dissolution behaviour of the various direct compression formulations reveal considerable variation according to the excipient used. After 45 minutes the tablets made from agglomerated lactose 80 and spray dried lactose produced dissolution profiles comparable to the original wet granulated material. These are followed by the partially pre gelatinised starch and then the microcrystalline cellulose with the lactose powder 200 and sieved lactose 80 exhibiting the slowest dissolution profiles for this drug. The agglomerated lactose 80 and spray dried lactose produced tablets with superior tensile strength compared to the wet granulate. Since the pharmacopoeial test for dissolution is taken at 45 minutes , it is feasible that the existing wet granulation step in the manufacture of this particular drug could be replaced by use of either agglomerated or spray dried lactose as a direct compression ingredient. This would be of considerable benefit to the manufacturer, saving process time and cost resulting in a more efficient manufacturing process with associated economic benefits.
The rapid compressibility approach demonstrates the benefit of determining the critical properties- tablet tensile strength and dissolution profile- of the various formulations with limited amounts of material. To perform such work using pilot scale equipment would have engaged the manufacturer’s equipment and personnel for a considerable length of time. Since all assessments were performed with milligram quantities of material the manufacturer saved time, material and costs whilst evaluating the widest range of formulations. The information gained is of great importance not only technically but from a business viewpoint.
Why use a Gamlen Tablet Press?
It can save you time, money and materials. People need help to study tablets under properly controlled conditions in a laboratory.
Michael Gamlen invented the Gamlen Tablet Press (GTP) to help you understand the relationship between the properties of your drug, formulation, and manufacturing process. When you do this you can develop better products more quickly, and improve productivity of your tablet manufacturing operations.
The GTP is the first machine designed to make tablets on a small scale at a user-specified compaction force. This force determines both the physical strength and the dissolution behaviour of the tablet. These are the key properties which ensure the tablet reaches the patient and delivers the drug.
The machine works by monitoring the force in real time using a PLC. The punch force and punch position are displayed in real time on a computer which is also used to input the compaction conditions. Using the GTP we make tablets of extraordinary reproducibility and consistency, within 1-2% force, and with no wastage. Batch yields are >99%.
For the measurement of tablet breaking load, the press records both force and displacement during both compression and fracture, and also provides the ejection force profile associated with tablet ejection
In the scale-up of tablet production, the press can be used to determine the relationship between tablets developed at the bench-top scale using a few grams of material (often at the early development stage) and the final tablet manufactured on a rotary tablet press. The latter uses hundreds of kilograms of material, making process development difficult because of practical difficulties in experimentation; smaller and different shaped tablets can, however, be scaled to the final desired tablet design if TFS is used as the basis for comparison.
If you want better tablet products and processes you need the Gamlen Tablet Press.
Using rapid compressibility assessment the time for formulation assessment is markedly reduced. Our studies have shown that multiple formulations can be assessed quickly at milligram scales allowing a manufacturer to determine possible efficiencies to their manufacturing process within the constraints of their license. The saving of time and material costs to a manufacturer and subsequent product decisions is of great significance.
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