by Michael Gamlen
Study demonstrates importance of material compressibility assessments in tablet drug development and manufacture.
Material compressibility (the inherent capability to tablet) influences drug substance properties such as adsorption, dissolution rate as well as hardness and friability.
Using a Gamlen D Series PCA, accurate measurement and data is provided, making the tableting process quick, robust and reliable.
The compressibility of pharmaceutical materials is a critical quality attribute of a tablet that determines the force needed to make the tablet. This in turn affects all tablet properties such as disintegration, dissolution and adsorption of the drug as well as physical properties such as hardness and friability. Many of the problems associated with tablet quality relate to the fact that the effect of material compressibility on tablet properties are not measured during development even though it is known to have considerable effect on drug dissolution and absorption as well as tablet hardness and friability.
Compressibility measurements were not routinely possible before but a new instrument called the Gamlen D Series PCA makes this now practical and affordable. Using this instrument, we illustrate in this article that compressibility assessments of tablet or compact properties made at key points through the tablet development and manufacturing process will assure quality of the final product.
The tablet development process
The modern tablet is a complex drug delivery system where the drug substance is combined with a number of excipients to aid formulation of the desired product. These include bulking agents, binders, disintegrants and coatings all of which have some function to aid the processing of the drug substance into the end product form. The excipients and drug substance are processed through a number of unit operations such as mixing, blending, granulation, tableting and often coating to form the final product (Figure 1).
Figure 1 Unit operations in a typical tableting process
The final tablet has to fulfil a number of characteristics including the ability to deliver the correct amount of drug substance into the patients system as well as possess physicochemical characteristics that make iteasy to handle, administer and store. These include a suitable size, hardness, texture and stability as well as taste and smell.
Process and formulation development of the desired tablet form is time consuming and complex because knowledge of excipient/ drug substance material properties and their relationship to the processing parameters by which the final product is made is limited, preventing a priori prediction of quality. Therefore the formulation process tends to be cyclical as in Figure 2.
Figure 2 The Formulation Cycle
This causes manufacturers particular problems in developing and producing the ideal tablet which satisfies both its therapeutic use and its requirement to be manufactured both efficiently and economically. Even small variations in material properties or process parameters can have profound effects on the final tablet quality. For more than 50 years the development and manufacture of tablets has followed a Quality by Testing (QbT) approach (Figure 3) whereby assurance of final product quality is controlled by using set specifications for raw material, drug substance and fixed process parameters.
Figure 3 Quality by Testing strategy for tablet product control
The specification parameters are set tightly to try to ensure consistency of the manufacturing process, and are fixed in the regulatory submission. If the finished drug product passes the tight specification the batch can be released to market- if not the batch is usually discarded.
The main criticism of this approach is that fundamental properties of the formulation are not understood and in the event of failure the root cause cannot be determined resulting in on-going losses of the product until either the root causes are understood and addressed or supplements to revise acceptance criteria or a modified process are approved by the regulatory authorities. Such tight specifications has resulted in tablet manufacturing being one of the most inefficient processes (Figure 4) – characterised as a three sigma process (66807 defects per million opportunities). Total reliance is placed on end product testing to provide patients with quality products at a six sigma level (considered the world class level with 3.4 cases of non-conformance per million opportunities)
Figure 4 Tablet manufacturing – an inefficient process
The use of a Quality by Design (QbD) approach to pharmaceutical development and manufacturing (Figure 5) is now being promoted by Regulatory Authorities. This requires a mechanistic understanding of process/material relationships by which the drug is developed and manufactured. Using such an approach should remove the need for end product testing as process understanding and/or process control will provide sufficient evidence that the batches will meet specification if tested.
Figure 5 The Quality by Design approach for tablet product control
However for tablet dosage forms, prediction of how process and material parameters relate to the final product is still not possible and extensive development work would be needed to take advantage of the approach. This, together with issues such as the investment in scientific understanding needed, and the organisational culture/ mind-set required to adopt such an apparently radical approach, has led to a lower uptake of the QbD approach than expected. Most companies are aware of the benefits of QbD – but faced with the level of knowledge required, many still prefer to retain the inefficient but familiar QbT approach to development.
With the increased commercial competition for markets driven by patent expiries and pressurised healthcare budgets, reliance on out moded strategies such as QbT will ultimately result in more business failures.
The measurement of material compressibility complements the QbD approach
Even though mechanistic models of tablet quality are not possible with today’s scientific knowledge, valuable empirical data can be gained by making appropriate compressibility measurements during the tablet development process. The approach will enable manufacturers to test systematically the effects on tablet quality of different process operations, process parameters and different materials. We have used the Gamlen D Series PCA to this effect. This newly developed instrument (Figure 6) is the World’s first computer controlled bench top tablet press. Lightweight at 16kg and portable the pressprovides real time Force/Displacement readings of material compressibility and ejection force.
Figure 6 Gamlen D Series PCA
Why use a Gamlen D Series PCA?
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 D Series PCA 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 Gamlen D Series PCA 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 Gamlen D Series PCA 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 D Series PCA.
Pre-formulation, formulation studies and manufacturing quality control using rapid compressibility assessments
The Gamlen D Series PCA can be been used at all stages of the tablet manufacturing process (Figure 7) to optimise drug substance and small scale formulations for tableting.
Figure 7 Rapid compressibility assessments at all stages of the tablet manufacturing process
At the pre-formulation stage of tablet product development, key information about the drug substance properties intrinsic to their processing and stability behaviour is generated including:
- Salt selection- the best salt that is physically and chemically stable, well absorbed as well as compressible.
- Morphic form -the importance of monitoring the effect of processing operations on drug substance morphic form is particularly important to final product quality e.g. the Norvir® case involved morphic form changes of the drug substance ritonavir (Abbott Laboratories) which had markedly different solubility properties.
- Intrinsic dissolution testing. The rate of drug dissolution of drug substance per unit area per unit time measured under sink conditions is used as a comparative test during compound or salt selection. In the example (Figure 8) we have shown using compacts made by the Gamlen D Series PCA how the intrinsic dissolution rates of the drug substance is affected by compaction force.
Figure 8 UV monitoring of intrinsic dissolution on compacts made on the Gamlen D Series PCA – compaction values in kg
The compacts were prepared in special dies so that the top surface only was exposed to the dissolution media. Online UV scanning gave rapid results without the need for a specific analytical method. The study shows that dissolution profile is affected by the compression force applied to the compact. These values are of significance in matching the desired dissolution profile of the final product with the tableting compression parameters.
Formulation studies using rapid compressibility assessment
In a recent study performed by Gamlen Tableting Limited we investigated, using rapid compressibility assessment, the effect of changing a wet granulated formulation of a well-known blood pressure medicine to a direct compression formulation. If this were possible, the cost/ efficiency savings to the manufacturer would be considerable. Regulatory changes would also be minimal since the qualitative formula would remain consistent within the terms of the license providing a simple change route.
Six different direct compression formulations were compared to the existing wet granulated formulation. 100mg of each formulation was compressed on the Gamlen D Series PCA at forces ranging from 100-400kg. The resulting compacts were then fractured on the Gamlen D Series PCA in its fracture mode to provide fracture strength details. From the tablet dimension and force applied the tensile strength of the tablet was calculated.
The compressibility assessments (Figure 9) showed clear differences between the formulations –some direct compression formulations (those with agglomerated lactose, microcrystalline cellulose and spray dried lactose) proving to have greater tensile strength than the existing formulation. Dissolution studies (Figure 10) then revealed that two direct compression formulations (containing agglomerated lactose and spray dried lactose) did give comparable dissolution profiles to the existing wet granulated formulation. The two formulations additionally produced tablets with superior tensile strength compared to the existing wet granulate. These formulations are more compressible than the existing wet granulate and will produce tablets with the desired dissolution profile at lower compression forces- a major advantage over the existing process.
Figure 9 Compressibility assessment of wet granulated and direct compression blends
Figure 10 Dissolution profile of the wet granulated and direct compression blends
The replacement of the wet granulation process and production of tablets at lower compression forces provide the manufacturer with considerable cost/material/time efficiencies for the production of this drug. In addition since the formulation has not changed qualitatively (the only change would be using agglomerated or spray dried lactose instead of the existing lactose used for wet granulation) the manufacturer is also provided with a simple regulatory change route.
Using the rapid compressibility assessment approach, we provided evidence to a manufacturer to make a strategic product decision quickly, accurately and with minimal quantities of material. We obtained valuable information as to the options available for the development and manufacturing of this particular product and are now in a position to manufacture pilot scale quantities of the material to confirm the studies. Without the use of the Gamlen D Series PCA the evaluation of the seven different formulations would have entailed more time, material and effort to come to the same conclusions.
Quality control of drug supply
The Gamlen D Series PCA was able to compare two suppliers of the drug substance amoxicillin – Figure 11. Using small quantities of the drug substance, a marked difference in compressibility was noted.
Figure 11 Compressibility differences between two suppliers of amoxycilin
The two batches from Supplier 1 exhibited lower compressibility but greater consistency than Supplier 2 batches. This study generated unique information on less than 1g of each lot of drug substance tested, which could not have been generated in any other way. It enabled the manufacturer to make informed decisions about suppliers and their suitability. These principles have widespread applications in many areas.
Whilst the mechanistic understanding of how tablets behave as a drug delivery vehicle is unlikely to be understood in the near future, we have shown that application of material compressibility assessments during the tablet development process provides relevant information which assures tablet quality. This is due to the fact that material compressibility – the inherent capability to tablet- influences drug substance properties such as adsorption and dissolution rate as well as tablet physical quality such as hardness and friability. Use of a compressibility instrument such as the Gamlen D Series PCA makes such measurements practical and affordable making the tableting process quick, robust and reliable.