Understanding the Roles of Excipients in Moisture Management in Solid Dosage Forms.

Excipients are ubiquitous in pharmaceutical products, and often, they can also play a critical role in maintaining product quality. For a product containing a moisture-sensitive drug, moisture can be deleterious to the product stability during storage. Therefore, using excipients that interact with moisture in situ can potentially alleviate product stability issues. In this study, the interactive behavior of starch with moisture was augmented by coprocessing maize starch with sodium chloride (NaCl) or magnesium nitrate hexahydrate [Mg(NO3)2·6H2O] at different concentrations (5 and 10%, w/w). The effect of the formulation on drug stability was assessed through the degradation of acetylsalicylic acid, which was used as the model drug. The results showed that coprocessing of the starch with either NaCl or Mg(NO3)2·6H2O impacted the number of water molecule binding sites on the starch and how the sorbed moisture was distributed. The coprocessed excipients also resulted in lower drug degradation and lesser changes in tablet tensile strength during post-compaction storage. However, corresponding tablet formulations containing physical mixtures of starch and salts did not yield promising outcomes. This study demonstrated the advantageous concomitant use of common excipients by coprocessing to synergistically mitigate the adverse effects of moisture and promote product stability when formulating a moisture-sensitive drug. In addition, the findings could help to improve the understanding of moisture-excipient interactions and allow for the judicious choice of excipients when designing formulations containing moisture-sensitive drugs.

Tableting of coated multiparticulates: Influences of punch face configurations.

The influences of the punch face design on multi-unit pellet system (MUPS) tablets were investigated. Drug-loaded pellets coated with sustained release polymer based on ethylcellulose or acrylic were compacted into MUPS tablets. Punch face designs used include standard concave, deep concave, flat-faced bevel edge and flat-faced radius edge. MUPS tablets compacted at 2 or 8 kN were characterized for their tensile strength. The extent of pellet coat damage after tableting was evaluated from drug release profiles. Biconvex tablets were weaker by 0.01-0.15 MPa, depending on the pellet type used, and had 1-17 % higher elastic recovery (p < 0.000) than flat-faced tablets. At higher compaction force, the use of the deep concave punch showed a 13-26 % lower extent of pellet coat damage, indicated by a relatively higher mean dissolution time, compared to other punch face configurations (p < 0.000). This was attributed to increased rearrangement energy of the compacted material due to the high punch concavity, which sequestered compaction stress exerted on pellet coats. Although the deep concave punch reduced the stress, the resultant tablets containing pellets coated with acrylic were weaker (p = 0.01). Overall, the punch face configuration significantly affected the quality of MUPS tablets.

Surface Modification of lactose carrier particles using a fluid bed coater to improve fine particle fraction for dry powder inhalers.

Surface roughness of carrier particles can impact dry powder inhaler (DPI) performance. There are opposing views on the effect of roughness on DPI performance. Hence, a systematic approach is needed to modify carrier surfaces and evaluate the impact on drug delivery. Carrier particle surfaces were modified by fluid bed coating with saturated lactose containing micronized lactose of different sizes (2, 5 and 8 µm) and coated to different levels (20, 40, 60 and 80%). Their drug delivery performance was assessed by the fine particle fraction (FPF). Roughness parameters, mean arithmetic roughness (Ra) and arithmetic mean height (Sa), of the carrier particles, were also evaluated using optical profilometry and scanning laser microscopy. Generally, particles of higher Ra had higher FPF. Higher Sa resulted in higher FPF only for particles with 60 and 80% coat levels. Reduced contact surface area between the drug particle and rougher carrier particle resulted in easier drug detachment during aerosolization. The 5 µm micronized lactose produced optimal carrier particles with respect to FPF and surface roughness. The study highlighted that with the ideal particles for surface roughening and coating level, surface roughening could be efficiently achieved by fluid bed coating for superior DPI performance.

Alginate-based matrix tablets for drug delivery.

INTRODUCTION: As a nature-derived polymer with swelling and gelling properties, alginate has found wide biopharma-relevant applications. However, there is comparatively limited attention on alginate in tablet formulations. Therefore, this review aimed to provide an overview of the applications of alginate in solid dosage form formulations. AREAS COVERED: This review outlines the role of alginate for oral sustained release formulations. For better insights into its application in drug delivery, the mechanisms of drug release from alginate matrices are discussed alongside the alginate inherent properties and drug properties. Specifically, the influence of alginate properties and formulation components on the resultant alginate gel and subsequent drug release is reviewed. Modifications of the alginate to improve its properties in modulating drug release are also discussed. EXPERT OPINION: Alginate-based matrix tablets is useful for sustaining drug release. As a nature-derived polymer, batch consistency and stability raise some concerns about employing alginate in formulations. Furthermore, the alginate gel properties can be affected by formulation components, pH of the dissolution environment and the tablet matrix micro-environment pH. Conscientious efforts are pivotal to addressing these formulation challenges to increase the utilization of alginate in oral solid dosage forms.

Relative Humidity Cycling: Implications on the Stability of Moisture-Sensitive Drugs in Solid Pharmaceutical Products.

The stability of a moisture-sensitive drug in tablet formulations depends particularly on the environment's relative humidity (RH) and the products' prior exposure to moisture. This study was designed to understand drug stability in relation to the moisture interaction of the excipients, moisture history of the tablets, and RH of the environment. The stability study was performed on tablets containing acetylsalicylic acid (ASA), formulated with common pharmaceutical excipients like native maize starch, microcrystalline cellulose (MCC), partially pregelatinized maize starch (PGS), dicalcium phosphate dihydrate (DCP), lactose, and mannitol. The tablets were subjected to storage conditions with RH cycling alternating between 53% and 75%. Results were also compared to tablets stored at a constant RH of 53% or 75%. The excipients demonstrated marked differences in their interactions with moisture. They could be broadly grouped as excipients with RH-dependent moisture content (native maize starch, MCC, and PGS) and RH-independent moisture content (DCP, lactose, and mannitol). As each excipient interacted differently with moisture, degradation of ASA in the tablets depended on the excipients' ability to modulate the moisture availability for degradation. The lowest ASA degradation was observed in tablets formulated with low moisture content water-soluble excipients, such as lactose and mannitol. The impact of RH cycling on ASA stability was apparent in tablets containing native maize starch, MCC, PGS, or DCP. These findings suggested that the choice of excipients influences the effect of moisture history on drug stability. The results from studies investigating moisture interaction of excipients and drug stability are valuable to understanding the inter-relationship between excipients, moisture history, and drug stability.

Ensuring Product Stability - Choosing the Right Excipients.

The stability of pharmaceuticals is an important product quality attribute. Of the known factors affecting stability, moisture is often perceived as the most common cause of drug degradation by hydrolysis or other reactions facilitated by moisture as a medium. Excipients are a critical entity in formulations to enable drug delivery as well as efficient manufacture of pharmaceutical dosage forms. Yet to this end, there is limited application and understanding of the role of excipients in protecting moisture sensitive drugs. An improved understanding of moisture-excipient interactions is important when selecting excipients for formulations containing moisture sensitive drugs. This review outlines the role of excipients as a moisture protectant in oral solid dosage forms. It focuses on the moisture interactions of excipients in order to highlight the potential of certain excipients as moisture protectants. More specifically, the mechanisms by which excipients can reduce drug degradation (e.g. acting as a physical barrier, reducing moisture availability and mobility) are discussed. A summary of analytical tools to evaluate moisture-excipient interactions is also provided.

Impact of Amylose-Amylopectin Ratio of Starches on the Mechanical Strength and Stability of Acetylsalicylic Acid Tablets.

The two main components of starch - amylose and amylopectin, are responsible for its interaction with moisture. This study investigated how moisture sorption properties of the starches with different amylose-amylopectin ratio impacted tablet properties including drug stability. The starch samples were equilibrated to 33, 53, and 75% relative humidity (RH) and then assessed for tabletability, compactibility, and yield pressure. Effect of humidity on viscoelastic recovery was also evaluated. Tabletability and compactibility of high-amylose starch were better than that of high-amylopectin starch at 33 and 53% RH. However, at 75% RH, the reverse was observed. In terms of yield pressure, high-amylose starch had lower yield pressure than high-amylopectin starch. High-amylose starch tablets also exhibited lower extent of viscoelastic recovery than high-amylopectin starch tablets. The variations in the tableting properties were found to be related to relative locality of the sorbed moisture. Degradation of acetylsalicylic acid in high-amylose starch tablets at 75% RH, 40°C was less than the tablets with high-amylopectin starch. This observation could be attributed to the greater amount of water molecules binding sites in high-amylose starch. Furthermore, most of the sorbed moisture of high-amylose starch was internally absorbed moisture, therefore limiting the availability of diffusible sorbed moisture for degradation reaction. Findings from this study could provide better insights on the influence of amylose-amylopectin ratio on tableting properties and stability of moisture-sensitive drugs. This is of particular importance as starch is a common excipient in solid dosage forms.

Investigation on the impact of different proportions of components in formulations on stability of a moisture sensitive drug.

Physicochemical and mechanical properties of tablets are largely dictated by formulation compositions. Different excipients possess different tableting and moisture sorption behaviors. Therefore, this study was designed to elucidate the relative influence of the proportion of components in formulations on tablet properties. Acetylsalicylic acid (ASA) tablets containing different proportions of starch, microcrystalline cellulose (MCC) and calcium hydrogen phosphate dihydrate (DCP) were prepared. The excipients were evaluated for their moisture sorption properties. Mechanical strength of the tablets was determined alongside with ASA stability, by storing the tablets at 75% RH, 25 °C. The stability study showed the importance of drug loading level on its stability. For a fixed ASA proportion, formulations with more starch were able to absorb more moisture and possessed larger areas of hysteresis loop in their moisture sorption isotherms. The presence of starch contributed positively to ASA stability although increasing proportions of starch compromised the tablet mechanical properties. Contrastingly, MCC produced mechanically stronger tablets as its plastically deforming and fibrous properties contributed to a good structural network. The findings provide a deeper understanding of the dichotomous effect by the proportion of components in formulations containing a moisture sensitive drug on drug stability and mechanical strength of the resultant tablets.

Insights into the Moisture Scavenging Properties of Different Types of Starch in Tablets Containing a Moisture-Sensitive Drug.

Starch is a commonly used excipient in the pharmaceutical industry. However, information on the effect of the moisture scavenging properties of starch to protect moisture-sensitive drugs is limited. The interaction between starch and moisture is of particular interest as moisture fugacity can impact drug stability. In this study, the moisture behavior of different starches was examined for an understanding of its role in the degradation of acetylsalicylic acid. The starches were characterized for their dimensional- and moisture-related properties. Stability testing was carried out on tablets containing acetylsalicylic acid and different starches. Although moisture sorption processes were visually comparable for the different starches, quantitative differences were found in their moisture interaction and distribution. From the sorption isotherms, moisture monolayer coverage and area of hysteresis were found to correlate well with the percentage of acetylsalicylic acid degradation. The lowest percentage of acetylsalicylic acid degradation was observed in starch that exhibited high monolayer coverage, large area of hysteresis, and good capacity for internally absorbed moisture. Findings from this study highlighted the value of moisture scavenging excipients when formulating moisture-sensitive drug products. Clearly, the assessment of moisture sorption properties of excipients during the preformulation phase can be an invaluable exercise for identifying the best possible ingredients in formulations where moisture sensitivity is an area of concern.

Insights on the role of excipients and tablet matrix porosity on aspirin stability.

Excipient-moisture interaction can be a critical attribute in determination of product stability. This study aimed to investigate influence of integrating excipients having different moisture interaction into moisture sensitive drug formulations. Aspirin was formulated with maize starch (MS), microcrystalline cellulose (MCC) and calcium hydrogen phosphate dihydrate (DCP). The excipients were evaluated for their inherent moisture content and water activity. Tablets fabricated at different compression pressures were exposed to 40 °C, 75% relative humidity for a stipulated period before analyzing for aspirin degradation. The results revealed that while MS had higher moisture content, the water activity was relatively low. Consequently, MS tablets had lower aspirin degradation than MCC and DCP tablets. In contrast, high water activity of DCP resulted in greater aspirin degradation. This was despite the low moisture content of DCP. Influence of tablet porosity on aspirin degradation was minimal. This illustrated the fugacity of moisture, possessing high thermodynamic activity and physical spatial delimitation would not suppress its distribution. The findings suggested that excipients possessing high water retentive capacity could potentially be useful as internal tablet desiccants by acting as a moisture scavenger. This study also highlights the importance of water activity in preformulation studies related to the choice of excipients.

Influence of spray nozzle aperture during high shear wet granulation on granule properties and its compression attributes.

The distribution of granulating liquid is known to affect the high shear wet granulation process but the impact of the spray nozzle attributes is still unclear. While homogenous liquid distribution can be achieved by using a spray nozzle, the effect of different nozzle aperture sizes on granule properties is not well understood. In this study, nozzles of different aperture sizes were used to introduce the granulating liquid in high shear wet granulation using different process parameters. Design of experiment approach was utilised to assess effect of process parameters on granule properties. Granules produced with different spray nozzles were evaluated for binder distribution inhomogeneity, size, shape, flowability and compression attributes such as tabletability and yield pressure. Coarser granules with better flow properties were produced using the smaller aperture size nozzle. On the other hand, granules had better tabletability and lower yield pressure when larger aperture size nozzle was used. Furthermore, size of granules produced by using larger aperture size nozzle was more affected by changes in the process variables which could be influenced by the differences in granulating liquid feed rate and spray droplet size. Although the granules aspect ratios were comparable across the nozzle aperture sizes, granules produced from smaller aperture size nozzle appeared to be rounder. Regardless of the nozzle aperture sizes, homogenous binder distribution was achieved. The findings from this study could be a useful guide to the selection of the appropriate nozzle aperture size in wet granulation.