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.

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.

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.

Conversion of liquid chitosan-based nanoemulsions into inhalable solid microparticles: Process challenges with polysaccharide.

Solid particles ≤5 µm are essential to allow lower lung deposition and macrophage phagocytosis of anti-tubercular drugs. Decorating liquid nanoemulsion of anti-tubercular drug with macrophage-specific chitosan and chitosan-folate conjugate and spray drying the nanoemulsion with lactose produced oversized solid particles due to polysaccharide binding effects. This study designed solid nanoemulsion using lactose as the primary solid carrier and explored additives and spray-drying variables to reduce the binding and particle growth effects of chitosan. Deposition of magnesium stearate on lactose negated chitosan-inducible excessive lactose-liquid nanoemulsion binding and solid particle growth. Moderating the adhesion of chitosan-decorated liquid nanoemulsion onto lactose produced smooth-surface solid microparticles (size: 5.45 ± 0.26 µm; roughness: ∼80 nm) with heterogeneous size (span: 1.87 ± 1.21) through plasticization of constituent materials of nanoemulsion and lactose involving OH/N-H, C-H, CONH and/or COO moieties. Smaller solid particles could attach onto the larger particles with minimal steric hindrance by smooth surfaces. Together with round solid particulate structures (circularity: 0.919 ± 0.002), good pulmonary inhalation beneficial for treatment of pulmonary tuberculosis as well as other diseases is conferred.

An evaluation of microcrystalline cellulose attributes affecting compaction-induced pellet coat damage through a multi-faceted analysis.

Pellet coat damage in multi-unit pellet system (MUPS) tablets has previously been studied and addressed with limited success. The effects of lactose filler material attributes on pellet coat damage have been relatively well-studied but a similar understanding of microcrystalline cellulose (MCC) is lacking notwithstanding its high cushioning potential. Hence, the relationships between MCC attributes and pellet coat damage were investigated. Single pellet in minitablets (SPIMs) were used to isolate pellet-filler effects and reveal the under-unexplored impact of risk factors found in MUPS tablets. MUPS tablets and SPIMs were prepared with various grades of MCC and pellets with an ethylcellulose or acrylic coat at various compaction pressures. Subsequently, the extent of pellet coat damage was determined by dissolution test and quantified using two indicators to differentiate the nature of the damage. A multi-faceted analytical approach incorporated linear regression, correlations and a classification and regression tree algorithm and evaluated how MCC attributes, such as flowability, particle size and plastic deformability, exert various influences on the extent of ethylcellulose and acrylic pellet coat damage. This analysis improved the understanding of the different mechanisms by which pellet coat damage to these two polymer types occurs which can help enhance future pellet coat damage mitigation strategies.

Nano-enabled agglomerates and compact: Design aspects of challenges.

Nanoscale medicine confers passive and active targeting potential. The development of nanomedicine is however met with processing, handling and administration hurdles. Excessive solid nanoparticle aggregation and caking result in low product yield, poor particle flowability and inefficient drug administration. These are overcome by converting the nanoparticles into a microscale dosage form via agglomeration or compaction techniques. Agglomeration and compaction nonetheless predispose the nanoparticles to risks of losing their nanogeometry, surface composition or chemistry being altered and negating biological performance. This study reviews risk factors faced during agglomeration and compaction that could result in these changes to nanoparticles. The potential risk factors pertain to materials choice in nanoparticle and microscale dosage form development, and their interplay effects with process temperature, physical forces and environmental stresses. To render the physicochemical and biological behaviour of the nanoparticles unaffected by agglomeration or compaction, modes to modulate the interplay effects of material and formulation with processing and environment variables are discussed.

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.

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.

A Mini-Review on Solid Lipid Nanoparticles and Nanostructured Lipid Carriers: Topical Delivery of Phytochemicals for the Treatment of Acne Vulgaris.

Acne vulgaris (acne) is one of the most common dermatological problems affecting adolescents and young adults. Although acne may not lead to serious medical complications, its psychosocial effects are tremendous and scientifically proven. The first-line treatment for acne is topical medications composed of synthetic compounds, which usually cause skin irritation, dryness and itch. Therefore, naturally occurring constituents from plants (phytochemicals), which are generally regarded as safe, have received much attention as an alternative source of treatment. However, the degradation of phytochemicals under high temperature, light and oxygen, and their poor penetration across the skin barrier limit their application in dermatology. Encapsulation in lipid nanoparticles is one of the strategies commonly used to deliver drugs and phytochemicals because it allows appropriate concentrations of these substances to be delivered to the site of action with minimal side effects. Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) are promising delivery systems developed from the combination of lipid and emulsifier. They have numerous advantages that include biocompatibility and biodegradability of lipid materials, enhancement of drug solubility and stability, ease of modulation of drug release, ease of scale-up, feasibility of incorporation of both hydrophilic and lipophilic drugs and occlusive moisturization, which make them very attractive carriers for delivery of bioactive compounds for treating skin ailments such as acne. In this review, the concepts of SLNs and NLCs, methods of preparation, characterization, and their application in the encapsulation of anti-acne phytochemicals will be discussed.

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.

Chitosan and its derivatives as polymeric anti-viral therapeutics and potential anti-SARS-CoV-2 nanomedicine.

The coronavirus pandemic, COVID-19 has a global impact on the lives and livelihoods of people. It is characterized by a widespread infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), where infected patients may develop serious medical complications or even face death. Development of therapeutic is essential to reduce the morbidity and mortality of infected patients. Chitosan is a versatile biomaterial in nanomedicine and exhibits anti-microbial, anti-cancer and immunomodulatory properties. This review highlights the progress in chitosan design and application pertaining to the anti-viral effects of chitosan and chitosan derivatives (hydroxypropyl trimethylammonium, sulfate, carboxymethyl, bromine, sialylglycopolymer, peptide and phosphonium conjugates) as a function of molecular weight, degree of deacetylation, type of substituents and their degree and site of substitution. The physicochemical attributes of these polymeric therapeutics are identified against the possibility of processing them into nanomedicine which can confer a higher level of anti-viral efficacy. The designs of chitosan for the purpose of targeting SARS-CoV-2, as well as the ever-evolving strains of viruses with a broad spectrum anti-viral activity to meet pandemic preparedness at the early stages of outbreak are discussed.

Critical clinical gaps in cancer precision nanomedicine development.

Active targeting strategy is adopted in nanomedicine for cancer treatment. Personalizing the nanomedicine in accordance with patients' omics, under the precision medicine platform, is met with challenges in targeting ligand and matrix material selection at nanoformulation stage. The past 5-year literatures show that the nanoparticulate targeting ligand and matrix material are not selected based upon the cancer omics profiles of patients. The expression of cancer cellular target receptors and metabolizing enzymes is primarily influenced by age, gender, race/ethnic group and geographical origin of patients. The personalized perspective of a nanomedicine cannot be realised with premature digestion of matrix and targeting ligand by specific metabolizing enzymes that are overexpressed by the patients, and unmatched targeting ligand to the majority of cell surface receptors overexpressed in cancer. Omics analysis of individual metabolizing enzyme and cancer cell surface receptor expressed in cancer facilitates targeting ligand and matrix material selection in nanomedicine development.

Exploring Intestinal Surface Receptors in Oral Nanoinsulin Delivery.

Subcutaneous and inhaled insulins are associated with needle phobia, lipohypertrophy, lipodystrophy, and cough in diabetes treatment. Oral nanoinsulin has been developed, reaping the physiologic benefits of peroral administration. This review profiles intestinal receptors exploitable in targeted delivery of oral nanoinsulin. Intestinal receptor targeting improves oral insulin bioavailability and sustains blood glucose-lowering response. Nonetheless, these studies are conducted in small animal models with no optimization of insulin dose, targeting ligand type and content, and physicochemical and molecular biologic characteristics of nanoparticles against the in vivo/clinical diabetes responses as a function of the intestinal receptor population characteristics with diabetes progression. The interactive effects between nanoinsulin and antidiabetic drugs on intestinal receptors, including their up-/downregulation, are uncertain. Sweet taste receptors upregulate SGLT-1, and both have an undefined role as new intestinal targets of nanoinsulin. Receptor targeting of oral nanoinsulin represents a viable approach that is relatively green, requiring an in-depth development of the relationship between receptors and their pathophysiological profiles with physicochemical attributes of the oral nanoinsulin. SIGNIFICANCE STATEMENT: Intestinal receptor targeting of oral nanoinsulin improves its bioavailability with sustained blood glucose-lowering response. Exploring new intestinal receptor and tailoring the design of oral nanoinsulin to the pathophysiological state of diabetic patients is imperative to raise the insulin performance to a comparable level as the injection products.

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.

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.

3D projection and multivariate image analysis for quantitative visual modelling of mixability and rheological behavior of lactose powder.

BACKGROUND: This study reports the use of multivariate time and image analysis of avalanche videographic data for quantitative visual modelling of mixability. Its usefulness, in mechanistically modelling a powder's rheological behavior in relation to mixing, was evaluated. METHODS: Particle size distribution (PSD) of a pharmaceutical grade lactose powder was modified to reflect commercially encountered variability. The PSD variants were rheologically distinct and had different mixability. Avalanche testing was performed on the modified lactose powders. Avalanche rheological properties (ARP) profiles and videos were collected for numerical and quantitative visual modelling, respectively. In quantitative visual modelling, videos captured were transformed into serial projected images. Important features of the projected images were extracted as eigen-images, to derive the avalanche rheological visual metric (ARVM). Mixability was modelled as a function of ARP or ARVM and the rotation speed. RESULTS: Relative to the ARP model, the ARVM models were highly interpretable. As a univariate expression of ARP, ARVM also possessed construct validity (r2 greater than 0.99, slope ≥ 0.96). Important rheological features of the lactose powders were holistically visualized within a single eigen-image which enabled the generation of simpler models (5 versus 34 variables for ARP model). The ARVM models predicted mixability of lactose powders with greater accuracy than the ARP model (relative root mean square error of external validation ≤ 3.30% versus 4.96%). CONCLUSIONS: Quantitative visual modelling is a viable alternative to purely numerical approaches. Most significantly, the model's interpretability and concreteness enable manufacturers to readily understand the risk posed by PSD variability on manufacturing processes and swiftly take pre-emptive actions, without being mired in multivariate data complexity. In addition, the use of quantitative visual approach in time series imaging, for studying and monitoring industrial processes, could also be explored.