Influence of talc and hydrogenated castor oil on the dissolution behavior of metformin-loaded pellets with acrylic-based sustained release coating.

Multi-unit pellet system (MUPS) is of great interest as it is amenable to customization. MUPS comprises multi-particulates, usually as pellets or spheroids, which can be coated with diffusion barrier coatings. One commonly used diffusion barrier coating is the methacrylic acid copolymer, which can be used as a taste masking, enteric or sustained release polymer. While the versatility of methacrylic acid copolymers makes them pliable for pellet coating, there are impediments associated with their use. Additives commonly required with this polymer, including plasticizer and anti-adherent, have been shown to weaken the film strength. The objective of this study was to investigate the impact of osmotic pressure within the core on the sustained release coat integrity and functionality. Hydrogenated castor oil (HCO) was chosen as the additive to be studied. Metformin-loaded pellets, prepared via extrusion-spheronization, were coated with ethyl acrylate and methyl methacrylate copolymer (Eudragit RS 30 D) containing talc, talc-HCO, or HCO to different coat thicknesses. Drug release was investigated using the USP dissolution apparatus 2 and an ultraviolet imager. The swelling of the pellets when wetted was monitored by video imaging through a microscope. When coated to 7.5 % coat weight gain, coats with HCO slowed down drug release more than the other pellets. The pellets also swelled the most, which suggests that they were more resistant to the osmotic pressure exerted by metformin. For drugs which exert high osmotic pressure, HCO can serve as an efficient alternative to talc in the preparation of methacrylic acid copolymer coatings.

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.

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.

Investigation on the effect of roller compaction on paracetamol.

Roller compaction is a popular dry granulation method that has been associated with loss of tabletability. In this study, the effect of roller compaction on a model brittle elastic material, paracetamol, was examined. Roller compaction of paracetamol was carried out at three roll force to examine the effects of roll force on the tablet compaction properties. Paracetamol granules consisting of small fragmented crystals were created through the process of roller compaction. A compaction simulator was used to produce tablets from a sieved fraction of roller compacted paracetamol and non-roller compacted paracetamol. Despite the higher elastic energy to plastic energy ratio observed with tablets produced from roller compacted granules of higher forces, the table tensile strength obtained was higher with a lower capping coefficient. At the same time, tablet elastic recovery was found to be lower for tablets produced using roller compacted paracetamol granules. Prefragmentation during roller compaction process helped to reduce the energy required for fragmentation during tablet compaction, increasing the energy available for bond formation. Roller compaction of brittle elastic materials may be a viable option for improving tablet tensile strength and reducing tablet capping.

Impact of die wall material on the mechanical properties of paracetamol tablets.

Tablet quality can be affected by material, configuration and design of the tooling which comprise punches and dies. Much research attention had centred around punches, with very little reported on the dies. Dies with modified bore lining materials or inserts are available for special applications. However, the influence of such die types on tablet properties and the compaction process has not been well studied. Often, the reason for selecting dies with harder lining material is for improved wear resistance. In this study, flat-faced and convex-faced tablets were produced from paracetamol granules using dies with different bore inserts. Tablet properties and response parameters of the compaction process were evaluated to understand the impact of die mechanical and surface properties on the compacts formed. Compaction pressure was found to have the greatest impact on tablet elastic recovery (r ≥ 0.96, p < 0.01 in all bivariate correlations) and thus affecting the tensile strength. Choice of die inserts could impact the mechanical properties of convex-faced paracetamol tablets, particularly at high compaction pressures.

Effects of Particle Surface Roughness on In-Die Flow and Tableting Behavior of Lactose.

Particle rearrangement takes place during the initial phase of tablet compaction. In this study, rough lactose particles were prepared by roller compaction, and their surface roughness modified by partial surface dissolution using a fluidized bed processor. Flow characteristics of the particles were determined using various flow methods, and their compaction characteristics studied using a compaction simulator with punches of different geometry and compaction pressure. Rougher particles demonstrated poorer compressibility and powder flow due to the higher interparticulate frictional forces required for particle movement. Rearrangement energy during tablet compaction was found to be correlated with compressibility (R2 = 0.92) and increased with surface roughness of the particles. Particle rearrangement was found to be dependent on interparticulate frictional forces, which could be measured using FT4 powder rheometer variable flow rate test and compressibility test. Plastic energy decreased as a result of the increased rearrangement energy requirements. Decrease in tensile strength as a result of decrease in plastic energy was not significantly different. Roller-compacted lactose particles produced tablets of higher tensile strength than crystalline lactose because of prefragmentation of the crystalline structure during roller compaction.

The Effects of Feed Frame Parameters and Turret Speed on Mini-Tablet Compression.

Die filling is a critical process step during tablet production as it defines the tablet weight. Achieving die fill consistency during production of mini-tablets, tablets with diameters ≤6 mm, is considerably more challenging. Although die filling in rotary presses had been studied in relation to the feed paddle design, paddle speed, and turret speed, it is unclear how these process variables could impact mini-tablet production and product properties. In this study, 1.8 and 3 mm mini-tablets were prepared using a rotary press with multiple-tip tooling using different process configurations. Mini-tablet weight variation within and across compaction cycles were determined using data from compression roller displacement and mini-tablet weight. Higher die fill densities were achieved with a flat feed wheel paddle and high paddle speed. This was attributed to better granule fluidization in the feed frame, which also increased the intercycle weight variation and reduced tensile strength. The turret speed did not impact mini-tablet properties significantly. Granule overlubrication in the feed frame potentially reduced mini-tablet tensile strength during compaction. The number of paddle passes in the die fill region was correlated to mini-tablet die fill performance. Findings from this study could provide better insights into the relationship between process variables and mini-tablet product quality.

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.

Investigation on the impact of powder arching in small die filling.

The flow of particulate materials is critical during processes such as mixing, compression and packing. Non-cohesive arching, a feature characteristic of coarse and free-flowing particles, has been studied extensively for silos and hoppers. However, the arching of powders during die fill has received much less attention. In this study, die fill performance of coarse and free-flowing nonpareils was evaluated using a specially designed die filling device in order to investigate the impact of non-cohesive arching during die fill under gravity flow. Through evaluating die fill performance, the arching phenomenon during dynamic conditions of die fill could be captured. Nonpareils with large particle size increased the likelihood of arching and caused poorer die fill performance for narrow orifices. In contrast, die fill in large orifices was generally better with larger particles due to reduced inter-particulate friction. Both particle size and size distribution influenced non-cohesive arching during die fill. Forced feeding did not appear to affect die fill performance and non-cohesive arching. A critical particle size range beyond which die fill performance would decrease, particularly for the narrow orifices, was identified. Findings from this study provided a better insight into non-cohesive arching during die fill.

Understanding effects of process parameters and forced feeding on die filling.

Die filling is a critical step during pharmaceutical tablet production and is still not well understood due to the rather complex interplay between particle attributes, die orifice diameter and fill energetics. While shoe-die filling models have been used to simulate die filling conditions, they typically lack the sophistication of the actual production-scale, feeder-based die filling conditions. The relationship between tableting process parameters and filling into die orifices of different diameters by powders of different flowabilities requires critical examination and understanding. In this study, a special die filling contraption was designed and custom-made to simulate the effects of gravity, suction and feeder paddle assistance as present in modern rotary tablet presses. Die fill performance was studied using powders with different flow properties. Suction impact was greatest on die fill, in particular, for small orifice diameters and less permeable powders. Effect of paddle velocity on die fill was greater for compressible powders and larger orifice diameters. In comparison to suction and paddle velocity, forced feeding did not significantly affect die fill performance. Relationship between process parameters and die fill performance was found to be highly dependent on the material and orifice diameter.

Comparative evaluation of powder flow parameters with reference to particle size and shape.

Powder flow is critical to the success of various pharmaceutical processes such as tableting and capsule filling. Despite a plethora of flow characterisation techniques and parameters available, powder flow still remains to be a not well understood subject. Inter-relationships between the various powder flow parameters in particular have not been well established. Furthermore, while it is known that particle size and shape are important determinants of powder flow, their relative impact on individual flow parameter is unclear. In this study, granules were evaluated for their flow properties using various characterisation methods. Through multivariate analysis, flow parameters were classified based on the underlying physical granule property. Angle of repose, Hausner ratio, shear cell parameters and avalanche flow were found to be affected primarily by powder cohesion, which was in turn determined by the smallest granule size fraction. On the other hand, powder compressibility and inter-particulate friction were the main factors underlying basic flow energy. Angle of internal friction was primarily affected by particle roundness and did not appear to describe powder bulk flow properties. This study showed that while the various flow characterisation techniques were different in terms of their applications, there were common physical attributes that governed the measurements.

Dissolution of fine particle fraction from truncated Anderson cascade impactor with an enhancer cell.

Dissolution testing for inhalers were previously conducted either on unfractionated drug-carrier powders or drug of specific aerodynamic particle size. In this study, the collection of the full fine particle fraction (FPF) was attempted on a single stage. Capsules containing 30 mg of 2% salbutamol sulfate (SS) was tested to have a FPF of 9 ±â€¯1% using the full set of Andersen cascade impactor (ACI) and a modified Rotahaler® capable of achieving 4.0 kPa pressure drop at 60 L/min air flow rate. A truncated ACI comprising the USP throat, pre-separator, stage 0, stage 4, stage F, polytetrafluoroethylene funnel (TF) and small collection plate (sCP) was found to be capable of achieving a FPF of 9% collected on TF and sCP. An adhesive tape was used to collect the FPF from the TF and sCP and held in place by an enhancer cell in a 200 mL round bottom vessel containing 50 mL Gamble's solution with 0.2 v/v, % Tween 80. Dissolution testing of SS and Seretide® showed burst release of SS and salmeterol while sustained release of fluticasone. This study demonstrated a reproducible method which may be used for evaluation of the full FPF of orally inhaled products.

Equilibria, kinetics and mechanism for the degradation of the cytotoxic compound L-NG-nitroarginine.

L-NG-nitroarginine (LNNA), an analog of L-arginine, is a competitive inhibitor of nitric oxide synthase which causes the selective reduction of blood flow to tumor cells. Despite the potential of LNNA to function as an adjuvant in cancer therapies, its poor solubility and stability have hindered the development of an injectable formulation of LNNA that is suitable for human administration. This work, for the first time, details a systematic study on the determination of equilibrium Ka constants and the rate law of LNNA degradation. The four Ka values of LNNA were determined to be 1.03, 1.10 × 10-2, 2.51 × 10-10, and 1.33 × 10-13 M. From the kinetic and equilibrium studies, we have shown that the deprotonated form of LNNA is the main form of LNNA that undergoes degradation in aqueous media at room temperature. The rate law of LNNA degradation was found to be first order with respect to OH- concentration and first order with respect to LNNA- concentration. The rate constant at 25 °C and 1 atm was determined to be 0.04453 M-1min-1. A base catalyzed mechanism of LNNA degradation was proposed based on the kinetic study. The mechanism was found to be very useful in explaining the discrepancies and changes of the rate law at different pH values. It is thus recommended that LNNA should be formulated as a concentrated solution in acidic conditions for maximum chemical stability during storage and be diluted with a basic solution to near physiological pH just before administration.

Understanding die fill variation during mini-tablet production.

Reproducibility of die fill during tablet production is critical to ensure consistent tablet drug content and mechanical attributes. In the production of mini-tablets, tablets smaller than 6mm, achievement of uniform die fill is much more challenging. Powder flow is often associated with die fill accuracy but this relationship has not been well characterised especially for mini-tablets. In this study, flow properties of different types of granules were characterised. Mini-tablets of 1.8 and 3mm diameters were prepared from the granules using a rotary press with multiple-tip compression tooling. A methodology was established to evaluate mini-tablet die fill variation within and across compaction cycles using data from compression roller displacement and mini-tablet weight. Both sizes of mini-tablets showed similar extents of inter-cycle weight variation that could be associated with granules' inter-particulate friction. However, smaller mini-tablets had higher intra-cycle weight variation due to their narrower die orifices. Multivariate and univariate analyses suggested that gravity fill influenced intra-cycle weight variation of 3mm mini-tablets while suction fill was associated with that of 1.8mm mini-tablets. Possible differences in die fill mechanisms between the mini-tablet sizes were identified and this provided a better insight into die fill variations during the production of mini-tablets.

Tablet compression tooling - Impact of punch face edge modification.

The influence of punch face edge geometry modification on tablet compression and the properties of the resultant tablets produced on a rotary press were investigated. The results revealed that tablets produced from the punches with radius edge face geometry consistently displayed better physical quality; higher tensile strength and lower capping tendency. Modification of the angled edge of the bevel face to the curved edge of the radius face, enabled deeper punch penetration in the die cavity during the compression cycle, bringing about greater compact densification. Improved die fill packing increased interparticulate bond formation and helped to dissipate destructive elasticity within the compact, consequently reduced tablet expansion during the decompression phase. The positive impact of punch face edge modification was also more noticeable at a higher turret speed. The application of the precompression force along with dwell time extension amplified the tableting performance of radius edge punch face design to a greater extent when compared to bevel edge punch face design. This could be attributed to the enhanced packing efficiency at both precompression and main compression stages.