Fernanda Onofre, Ph.D. - Americas Applications Leader, IFF Pharma Solutions
Kevin O’Donnell, Ph.D. - R&D Leader, Pharma Solutions, IFF Pharma Solutions, IFF
One of the most common pharmaceutical dosage forms in drug delivery is the tablet; they’re a favorable dosage form for several reasons: dosing accuracy, physical and chemical stability, competitive production costs, high level of patient compliance and more.
Traditionally, manufacturers have relied on the well-established wet granulation process for tableting. While it’s effective, wet granulation is a time-consuming technique that can be costly and can lead to product cross-contamination or material loss during manufacturing.
Many manufacturers seeking to save time and money, improve efficiency and respond quickly to market changes, have already made the transition from wet granulation to direct compression (DC). The resource saving technique has evolved in the past few decades to inspire wide adoption throughout the pharmaceutical community. As the most straightforward manufacturing option with the fewest manufacturing steps, DC is the easiest to control manufacturing process for tablets, as well as the most cost-effective.
Direct Compression Refresher
The direct compression tablet process uses two primary process steps: blending the powdered active pharmaceutical ingredient (API) with excipients and compressing the finished tablets. No additional steps such as granulation or drying are required.
Apart from process simplicity, the key advantages of direct compression versus wet granulation include reduced capital, labor and energy costs for manufacture, and the avoidance of water addition, which can have implications on drug product stability. Despite the simplicity of the process, tableting via DC presents new challenges manufacturers should be prepared for, and formulators must anticipate.
Anticipating the Challenges
Though DC involves only a few process steps, product design can be challenging due to numerous competing objectives: the compression mix must flow to ensure a consistent tablet weight, yet it must also compress and compact into robust tablets, resulting in stable, effective tablets. For many formulators, facing complications such as poor flowability, inconsistent tablet weight, unsatisfactory tablet strength, lack of content uniformity or segregation and dissolution failure, are all too common.
These challenges can often be easily mitigated by incorporating the right excipients into the formulation. Excipients - such as fillers, binders and lubricants - play a significant role in a formulation’s content uniformity, flow and compaction properties, as well as their tensile strength. However, not all excipients hold up well during the DC process, which makes the selection of ingredients critical. By leveraging the right excipients in DC, manufacturers can combat these challenges and develop robust, cost-effective formulations.
Generally, excipients confer critical functionality to the powder blend that will be converted into tablets - compactability, flowability, disintegration properties, lubrication, and dissolution. Additionally, excipients’ physical and chemical compatibility with the API is essential. The stability of the API with the excipients is investigated in pre-formulation studies through thermal methods such as differential scanning calorimetry, forced degradation studies well defined in the industry and by aging both API and excipients under controlled conditions of heat and relative humidity.
Keeping the Powder Flow
The DC manufacturing process begins with the blending stage followed by feeding into the hopper. Inconsistent feeding of the blend into the tablet press can result in variations in tablet weight and API dosage. Powder flow is linked to particle morphology and particle size, amongst other characteristics. The choice of larger particle size excipients, or particles with more rounded characteristics or less fibrous, can positively impact powder flow. The powder blend should flow smoothly into the tablet press, but not uncontrollably as to “flood” the feed frame. Appropriate flow results in lower cost of production and more consistent product performance for patients.
Expertise in Co-Processed Excipients
In addition to powder flow, compactability is an essential property to obtain robust tablets. Without proper compactability, there may be unacceptable deviations in tablet hardness which may cause physical defects in the tablets leading to batch rejection and loss of capital.
As the demands of excipients change throughout the DC process, using advanced ingredients that deliver multiple functionalities help manufacturers save time and money. Co-processed excipients - which include a combination of two to three excipients - offer multiple functionalities that exceed or build upon conventional excipients.
Research shows that silicified microcrystalline cellulose (SMCC) - a co-processed blend of MCC and colloidal silicone dioxide-possesses the necessary qualities to improve powder flow, as well as compactability. Of the celluloses, MCC is the substance most often used in tableting as a dry binder and filler. In addition, colloidal silicone dioxide provides superb flowability and enhanced tablet strength.
SMCC performs favorably in terms of compactability and flowability, both of which contribute to robust, uniform formulations. This excipient also reduces wear on tooling equipment by reducing tablet compaction pressure. The degree of which powder flow and compactability have implications on DC must be considered - as well as lubrication, disintegration and dissolution.
However, depending on which challenge a manufacturer struggles with, additional excipients incorporated into the formulation might help. For example, sodium stearyl fumarate is an exceptional lubricant that can cleanly facilitate the ejection of tablets from machinery, and does not have a significant negative impact on tablet compaction. Furthermore, croscarmellose sodium is a disintegrant used in low concentrations that improves tablet disintegration and speeds up the dissolution of drugs.
Finding the Flow and Compaction During Excipient Application
Poorly soluble drugs, orally disintegrating tablets (ODTs) and effervescent dosage forms typically require a more hydrophilic lubricant. Tablets are susceptible to cracking and breaking when ejected from metal surfaces. In addition, friction impacts mechanical stability and flowability. When particles are subjected to large amounts of friction, such as through shear, it may result in a change in particle morphology or size. Lubricants are used to ensure a clean ejection with little friction, but can present a problem for tablet compaction.
In the past, formulators have typically selected magnesium stearate to meet their needs, a well-established lubricant for oral solid dosage forms. However, previous studies demonstrate magnesium stearate’s negative impact on dissolution and disintegration. Sodium stearyl fumarate is a lubricant that may solve each of these challenges when used in DC. It’s been shown to not significantly affect compactability and tablet tensile strength, and have less interference with disintegration time and dissolution. Sodium stearyl fumarate can withstand prolonged mixing (i.e., one-step mixing), while also maintaining these properties, which is extremely beneficial during a DC process.
Improved mechanical strength is a huge plus, both for improved post[1]tableting processes like coating or packaging, and for consistent API release. High-dose tablets may lack sufficient tensile strength if the API is not easily compactable. On the other hand, low-dose formulations might be hard to blend uniformly.
Tablets manufactured via DC are also susceptible to segregation prior to pressing, which can cause an unpredictable API release. It’s caused by separated and varying particle sizes upon exposure to external forces, like vibration. This results in significant variations in content uniformity and tablet weight.
While sodium stearyl fumarate contributes to improved compactability during formulation and compaction when compared to other lubricants, excipients are ultimately responsible to bind the API, fillers and other excipients. An effective binder is a must-have for tablet robustness, consistency and performance.
A Precise Delivery
Among the few disadvantages of tablets as a dosage form, consistent dissolution profile stands out. In this scenario, dissolution must precede absorption of the active ingredient. Tablets formulated for immediate release should disintegrate rapidly and consistently after ingestion to deliver the active ingredient quickly. Inconsistent dissolution could lead to varying levels of drug available for absorption, which ultimately reduces the efficacy of the dosage form. On the other hand, dose dumping of an API in a controlled release formulation can result in adverse toxic effects for the patient.
Croscarmellose sodium is a disintegrant that can be used at very low levels to achieve desired disintegration profiles in tablets made by DC. The amount of croscarmellose sodium used depends on tablet formulation, but usually ranges from 2-3%. Solubility of a major tablet component, either the drug or excipients, significantly affects the rate and mechanism of tablet disintegration. Tablets composed primarily of water-soluble ingredients tend to dissolve rather than disintegrate, resulting in relatively longer disintegration times. Tablets containing insoluble drugs and excipients often disintegrate rapidly if sufficient disintegrant is present, such as croscarmellose sodium.
Tablets Made Easier
The pharmaceutical industry recognizes the advantages of DC, especially when it comes to reducing complexity and improving throughput. By understanding the functionalities that make DC perform well, manufacturers will be prepared to make the transition and tap into a variety of excipient options that help solve their challenges at every stage of the processes.
Furthermore, by understanding excipient properties and their performance under various conditions, and selecting the right solution, the DC process is ultimately streamlined and simplified. By taking incremental steps to improve the manufacturing process, formulators can improve quality, efficiency and, by extension, inspire greater industry adoption.
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