Mannitol-coated hydroxypropyl methylcellulose as an alternative directly compressible controlled release excipient.

One of the most common forms of controlled release technology for oral drug delivery comprises an active ingredient dispersed in a hydrophilic matrix forming polymer such as hydroxypropyl methylcellulose (HPMC), which is tableted via direct compression. However, HPMC may pose problems in direct compression due to its poor flowability. Hence, mannitol syrup was spray-coated over fluidized HPMC particles to produce co-processed HPMC-mannitol at ratios of 20:80, 50:50, and 70:30. Particles of pure HPMC, co-processed HPMC-mannitol, and respective physical mixtures were evaluated for powder flowability, compression profiles, and controlled release performance. It was found that co-processed HPMC-mannitol consisted of particles with improved flow compared to pure HPMC particles. Sufficiently strong tablets of >2 MPa could be produced at moderate to high compression forces of 150-200 MPa. The dissolution profile could be tuned to obtain desired release profiles by altering HPMC-mannitol ratios. Co-processed HPMC-mannitol offers an interesting addition to the formulator's toolbox in the design of controlled release formulations for direct compression.

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.

Elucidating the effect of salt incorporation in tablets on tablet disintegratability.

The disintegration of tablets plays a crucial role in facilitating drug release, and disintegrants are used in tablet formulations to promote the disintegration process. This study aimed to explore and understand the impact of salt incorporation on tablet disintegratability. The study was designed to modulate the microenvironment temperature of tablets through dissolution of salts incorporated in the formulation, with the aim to facilitate tablet disintegration. It was observed that the incorporation of salts generally prolonged tablet disintegration. The impact of incorporating salts on tablet properties was both concentration-dependent and multi-factorial. The observed effect of salts on tablet disintegration was likely influenced by a combination of factors, including different properties of the salts, enhanced solubility of components, the temperature difference between the tablet and the disintegration medium, the expansion of air resulting from increased microenvironment temperature, and the competition for water between salts and disintegrants. These factors collectively contributed to the overall impact of salts on tablet disintegration.

Study of compaction tools and parameters on critical quality attributes of high drug load minitablets.

Minitablets are prepared using multiple die openings and multi-tip punches for greater productivity. With multiple tips on the punch barrel, the overall compaction force to be applied is commonly estimated by multiplying the desired compaction force per tip by the number of punch tips. Few researchers have however examined this proportionality and the effects of the number of punch tips and punch face geometry on the critical quality attributes (CQAs) of high drug load minitablets. In this study, the minitablets prepared by multi-tip tools exhibited greater weight variation than those prepared by single-tip tools. Their compaction was accompanied by a longer dwell time that led to a higher minitablet tensile strength and consequently a longer disintegration time. The compaction forces required to achieve a consistent set of minitablet CQAs were not directly proportional to the number of punch tips used. In comparison, the effect of punch face geometry was negligible. Increasing concentration of magnesium stearate (as lubricant) from 0.75 to 1.25 %, w/w reduced weight variation, especially of minitablets prepared by the multi-tip tools. It also increased the disintegration time but had no significant effect on the tensile strength of the minitablets regardless of type of tools used. The adjustment of compaction speed was an effective compensatory method to mitigate the differences in dwell time and tensile strength between minitablets prepared by single-tip and multi-tip standard concave tools. A larger reduction in compaction speed of the single-tip tools was required at higher compaction pressures.

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.

Study of diminutive granules as feed powders for manufacturability of high drug load minitablets.

The maximal amount of drug contained in a minitablet is limited. To reduce the total number of minitablets in a single dose, high drug load minitablets can be prepared from high drug load feed powders by various pharmaceutical processing techniques. Few researchers have however examined the influence of pharmaceutical processing techniques on the properties of high drug load feed powders, and consequently the manufacturability of high drug load minitablets. In this study, silicification of the high drug load physical mix feed powders alone did not yield satisfactory quality attributes and compaction parameters to produce good quality minitablets. The abrasive nature of fumed silica increased ejection force and damage to the compaction tools. Granulation of fine paracetamol powder was crucial for the preparation of good quality high drug load minitablets. The diminutive granules had superior powder packing and flow properties for homogenous and consistent filling of the small die cavities when preparing minitablets. Compared to the physical mix feed powders for direct compression, the granules which possessed higher plasticity, lower rearrangement and elastic energies, yielded better quality minitablets with high tensile strength and rapid disintegration time. High shear granulation demonstrated greater process robustness than fluid bed granulation, with less discernment on the quality attributes of feed powder. It could proceed without fumed silica, with the high shear forces reducing interparticulate cohesivity. An in-depth understanding on the properties of high drug load feed powders with inherently poor compactability and poor flowability is important for the manufacturability of high drug load minitablets.

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.

Tablet Disintegratability: Sensitivity of Superdisintegrants to Temperature and Compaction Pressure.

Tablet disintegration is an important pre-requisite for drug dissolution and absorption. The disintegration test is typically conducted at 37 °C, but the intragastric temperature may vary due to meals or fever. This study investigated the effects of temperature and compaction pressure on tablet disintegratability to gain deeper insights into superdisintegrant sensitivity and function. Tablets with either sodium starch glycolate or crospovidone as disintegrant were prepared at various compaction pressures and subjected to the disintegration test using different medium temperatures. Preheating of tablets was also employed to establish instant temperature equilibrium between the tablet and the disintegration medium. Liquid penetration and disintegration were faster as the medium temperature increased or compaction pressure decreased. Swelling or strain recovery disintegrants exhibited similar sensitivity to variations in the medium temperature. Preheating of the tablets resulted in slower disintegration, but this effect was reversible upon cooling, hence the slower disintegration was unlikely to be attributed to changes in the disintegrant physical state. The temperature difference between the tablet and the disintegration medium likely affected the rate of fluid flow into tablets and influenced disintegration. Understanding disintegrant temperature sensitivity would help to avoid unacceptable fluctuations in disintegration due to temperature variations. The temperature difference effect could also be harnessed to boost disintegrant performance.

MUPS Tableting-Comparison between Crospovidone and Microcrystalline Cellulose Core Pellets.

Multi-unit pellet system (MUPS) tablets were fabricated by compacting drug-loaded pellets of either crospovidone or microcrystalline cellulose core. These pellets were produced by extrusion-spheronization and coated with ethylcellulose (EC) for a sustained drug release function. Coat damage due to the MUPS tableting process could undermine the sustained release function of the EC-coated pellets. Deformability of the pellet core is a factor that can impact the extent of pellet coat damage. Thus, this study was designed to evaluate the relative performance of drug-loaded pellets prepared with either microcrystalline cellulose (MCC) or crospovidone (XPVP) as a spheronization aid and were comparatively evaluated for their ability to withstand EC pellet coat damage when compacted. These pellets were tableted at various compaction pressures and pellet volume fractions. The extent of pellet coat damage was assessed by the change in drug release after compaction. The findings from this study demonstrated that pellets spheronized with XPVP had slightly less favorable physical properties and experienced comparatively more pellet coat damage than the pellets with MCC. However, MUPS tablets of reasonable quality could successfully be produced from pellets with XPVP, albeit their performance did not match that of vastly mechanically stronger pellets with MCC at higher compaction pressure.

Effect of drug load and lipid-wax blends on drug release and stability from spray-congealed microparticles.

This study was designed to evaluate paraffin wax as a potential controlled release matrix for spray congealing and its impact on drug release and stability of the microparticles. Paraffin wax can form a hydrophobic barrier to moisture and reduce drug degradation besides retarding drug release in the gastrointestinal tract. More hydrophilic lipid-based additives can be incorporated to modulate the drug release through the paraffin wax barrier. This study reports the findings of lipid-wax formulations at preserving the stability of moisture-sensitive drugs in spray-congealed microparticles. Aspirin-loaded microparticles formulated with different drug loads, lipid additives, and lipid:wax ratios were produced by spray congealing. Stearic acid (SA), cetyl alcohol (CA), and cetyl ester (CE) were the lipid additives studied. The microparticles were evaluated for yield, encapsulation efficiency, particle size, drug stability, and release. CE exhibited the greatest effect on increasing drug release, followed by CA and SA. Dissolution profiles showed the best fit to Weibull kinetic model. The degree of drug degradation was low, with CA imparting the least protective effect, followed by SA and CE. Paraffin wax is useful for preserving the stability of moisture-sensitive aspirin and retarding its release from spray-congealed microparticles. The addition of lipid additives modulated drug release without compromising drug stability.

Charge reduction assisted production of diminutive fluid bed granules for high drug load minitablets.

Micronized drug powders are generally unsuitable as tableting feed to produce minitablets due to their cohesivity and poor flow. The silicification of fine paracetamol powder (PCMF) with an optimal concentration range of fumed silica (fSi) [0.7-0.9%, w/w] reduced the net negative charge of PCMF and improved powder flow. The optimal fSi concentration range suitable was established through the measurement of charge and flowability of the silicified powders. Silicification of PCMF by physical mix did not satisfactorily overcome the cohesive forces between the PCMF crystals and improve powder flow sufficiently such that it will feed consistently into the smaller die orifices during tableting. Using a specialized fluid bed system with swirling air and side spray, controlled granulation of silicified PCMF packed and agglomerated the interlocking-prone needle shaped PCMF crystals into diminutive granules that are more spherical and free flowing. With optimized fSi concentration (≈ 0.8%, w/w) and granulation process parameters, high drug load diminutive granules (D50≃ 90 µm) were successfully prepared from PCMF as starter seeds (D50≃ 30 µm). Minitablets prepared from the diminutive granules had low weight variation, and were mechanically strong with disintegration time of <30 s. This study demonstrated the feasibility of producing high drug load minitablets from a cohesive, electrostatic-prone fine drug powder.

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.

Effect of excipient particle size distribution variability on compact tensile strength; and its in-line prediction by force-displacement and force-time profiling.

BACKGROUND: Direct compression is potentially sensitive to particle size distribution (PSD) variability in pharmaceutical grade excipients. Yet, the impact is insufficiently studied. Furthermore, the use of force sensor as a process analytical technology (PAT) platform, to monitor the effect of PSD variations on compact tensile strength, is a readily available but underutilized strategy. METHODS: To address these shortfalls, the effect of PSD variability on compaction was investigated. Low (4% w/w drug) and high (15% w/w drug) dose blends comprising chlorpheniramine, microcrystalline cellulose and spray-agglomerated lactose were tableted. The PSD of spray-agglomerated lactose was varied by adding ungranulated fines to simulate commercially-relevant variability. Tensile strength and disintegration time were determined. The use of force sensor, to generate force-displacement and force-time profiles, for in-line tensile strength prediction was evaluated. RESULTS: Increasing proportion of ungranulated fines (≥ 16%) reduced tensile strength by 10% and 4% in low and high dose formulations (p < 0.02). Increased friction during compaction hindered particle movement and reduced the energy available for bonding. Nevertheless, disintegration performances were equally acceptable for immediate drug release (≈ 30 s). Modelling of tensile strength with force-displacement and force-time profiles yielded ≥ 98% accuracy for in-line prediction (relative root mean square error of prediction = 3.7% and 4.8%). CONCLUSION: A better understanding of the relationship between PSD variability and direct compression was attained; and force-displacement and force-time profiling are pragmatic and elegant PAT strategies. Significantly, with further refinements, the force sensor in the rotary tablet press can be repurposed for process monitoring and quality inspection. This unlocks opportunities for process understanding and control, without additional investments in PAT platforms.

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.

De-risking excipient particle size distribution variability with automated robust mixing: Integrating quality by design and process analytical technology.

BACKGROUND: Particle size distribution (PSD) variability in excipients affects mixing. In response, manufacturers rely on raw material control and rigidly defined process parameters to achieve quality. However, this status quo is costly; and diverges from regulatory exceptions for process robustness. Although robustness improves cost and material usage efficiency, it remains under-adopted. METHOD: To address this gap, a robust batch mixing operation that mitigated the impact of PSD variability was evaluated, with blends comprising chlorpheniramine, microcrystalline cellulose and lactose. PSD of lactose was varied to simulate commercially-relevant variability. Due to PSD-induced rheological variations, the blends had different optimal mixing speeds. For the automation study, near infrared (NIR) spectroscopy; process optimization and endpoint detection algorithms; and control hardware were integrated within a cluster of software environments. NIR spectroscopy was employed for in-line PSD characterization and blend monitoring, to modulate mixing speed and detect endpoint (feedforward and feedback control). RESULTS: NIR spectroscopy rapidly detected PSD variations by the 6th-9th rotations, to activate feedforward control, which mitigated the effect of PSD variability and reduced the mixing time by 13-34%. Endpoints were correctly detected. PSD variations and blend homogeneity were accurately predicted (relative standard error of prediction ≤ 2%). CONCLUSION: The automated robust mixing operation was successful. Pertinently, NIR spectrometer can be adopted for multimodal sensing. Its applicability for production-driven characterization of raw materials in batch and continuous pharmaceutical processing should be further explored. Lastly, this study laid the groundwork for end-to-end implementation of process analytical technology in robust batch processing.

Cushioning pellets based on microcrystalline cellulose - Crospovidone blends for MUPS tableting.

Compaction of multiple-unit pellet system (MUPS) tablets has been extensively reported to be potentially challenging. Thus, there is a need for non-segregating cushioning agents to mitigate the deleterious effect of the compaction forces. This study was designed to investigate the use of porous pellets as cushioning agents using different drying techniques to prepare pellets of various porosities and of different formulations. The pellets fabricated were characterized for their porosity and crushing strength. Subsequently, MUPS tablets were prepared using blends of polymer-coated pellets and custom-designed cushioning pellets by compacting at different pressures. The effects of pellet volume fraction and dwell time on the pellet coat damage, as well as the tensile strength of the resultant MUPS tablets were also investigated. Compacts with coated pellet volume fraction of 0.21 exhibited the best cushioning effect when tableted at different compression speeds with both gravity and force feeders. The findings from this study showed that cushioning pellet porosity was highest when drying was carried out by freeze drying, followed by fluid bed drying and oven drying. There was an inverse relationship between cushioning pellet porosity and strength. The tensile strength of tablets prepared from freeze dried pellets was highest. The protective effect of the cushioning pellets was principally dependent on their porosity. Also, pellet volume fraction in the compacts and compaction pressure used had remarkable effect on pellet coat damage. When unprocessed powders were compacted by automatic die filling, capping and lamination problems were observed. However, tablets of reasonable quality were made with the cushioning pellets. Freeze dried pellets containing crospovidone were found to be promising as cushioning agents and had enabled the production of MUPS tablets even at higher compaction pressures, beyond the intrinsic crushing strength of the coated pellets.