Development of a Controlled Continuous Low-Dose Feeding Process.

This paper proposes a feed rate control strategy for a novel volumetric micro-feeder, which can accomplish low-dose feeding of pharmaceutical raw materials with significantly different powder properties. The developed feed-forward control strategy enables a constant feed rate with a minimum deviation from the set-point, even for materials that are typically difficult to accurately feed (e.g., due to high cohesion or low density) using conventional continuous feeders. Density variations observed during the feeding process were characterized via a displacement feed factor profile for each powder. The characterized effective displacement density profile was applied in the micro-feeder system to proactively control the feed rate by manipulating the powder displacement rate (i.e., computing the feed rate from the powder displacement rate). Based on the displacement feed factor profile, the feed rate can be predicted during the feeding process and at any feed rate set-point. Three pharmaceutically relevant materials were used for the micro-feeder evaluation: di-calcium phosphate (large-particle system, high density), croscarmellose sodium (small-particle system, medium density), and barium sulfate (very small-particle <10 µm, high density). A significant improvement in the feeding performance was achieved for all investigated materials. The feed rate deviation from the set-point and its relative standard deviation were minimal compared to operations without the control strategy.

Probing the Molecular-Level Interactions in an Active Pharmaceutical Ingredient (API) - Polymer Dispersion and the Resulting Impact on Drug Product Formulation.

PURPOSE: An investigation of underlying mechanisms of API-polymer interaction patterns has the potential to provide valuable insights for selecting appropriate formulations with superior physical stability and processability. MATERIALS AND METHODS: In this study, copovidone was used as a polymeric carrier for several model compounds including clotrimazole, nifedipine, and posaconazole. The varied chemical structures conferred the ability for the model compounds to form distinct interactions with copovidone. Rheology and nuclear magnetic resonance (NMR) were combined to investigate the molecular pattern and relative strength of active pharmaceutical ingredient (API)-polymer interactions. In addition, the impact of the interactions on formulation processability via hot melt extrusion (HME) and physical stability were evaluated. RESULTS: The rheological response of an API-polymer system was found to be highly sensitive to API-polymer interaction, depending both on API chemistry and API-polymer miscibility. In the systems studied, dispersed API induced a stronger plasticizer effect on the polymer matrix compared to crystalline/aggregated API. Correspondingly, the processing torque via HME showed a proportional relationship with the maximum complex viscosity of the API-polymer system. In order to quantitatively evaluate the relative strength of the API-polymer interaction, homogeneously dispersed API-polymer amorphous samples were prepared by HME at an elevated temperature. DSC, XRD, and rheology were employed to confirm the amorphous integrity and homogeneity of the resultant extrudates. Subsequently, the homogeneously dispersed API-polymer amorphous dispersions were interrogated by rheology and NMR to provide a qualitative and quantitative assessment of the nature of the API-polymer interaction, both macroscopically and microscopically. Rheological master curves of frequency sweeps of the extrudates exhibited a strong dependence on the API chemistry and revealed a rank ordering of the relative strength of API-copovidone interactions, in the order of posaconazole > nifedipine > clotrimazole. NMR data provided the means to precisely map the API-polymer interaction pattern and identify the specific sites of interaction from a molecular perspective. Finally, the impact of API-polymer interactions on the physical stability of the resultant extrudates was studied. CONCLUSION: Qualitative and quantitative evaluation of the relative strength of the API-polymer interaction was successfully accomplished by utilizing combined rheology and NMR. Graphical Abstract.

Performance Evaluation of a High-Precision Low-Dose Powder Feeder.

Highly potent active pharmaceutical ingredients (APIs) and low-dose excipients, or excipients with very low density, are notoriously hard to feed with currently available commercial technology. The micro-feeder system presented in this work is capable of feeding low-dose rates of powders with different particle sizes and flow properties. Two different grades of lactose, di-calcium phosphate, croscarmellose sodium, silicon dioxide, a spray-dried intermediate, and an active ingredient were studied to vary material properties to test performance of the system. The current micro-feeder system is a volumetric feeder combined with a weighing balance at the outlet that measures feeder output rates. Feeding results are shown as a so-called "displacement-feed factor" curve for each material. Since the powder mass and volume are known in the micro-feeder system, in this work, we characterized an observed density variation during processing via a "displacement-feed factor" profile for each of the fed powders. This curve can be later used for calibrating the system to ensure an accurate, constant feed rate and in addition predicting feeding performance for that material at any feed rate. There is a relation between powder properties and feeding performance. Powders with finer particles and higher compressibility show densification during their feeding process. However, powders with larger particles and lower compressibility show both "densification" and "powder bed expansion," which is the manifestation of dilation and elastic recovery of particles during the micro-feeding process. Through the application of the displacement-feed factor, it is possible to provide precise feeding accuracy of low-dose materials.

Rheology Guided Rational Selection of Processing Temperature To Prepare Copovidone-Nifedipine Amorphous Solid Dispersions via Hot Melt Extrusion (HME).

The production of amorphous solid dispersions via hot melt extrusion (HME) relies on elevated temperature and prolonged residence time, which can result in potential degradation and decomposition of thermally sensitive components. Herein, the rheological properties of a physical mixture of polymer and an active pharmaceutical ingredient (API) were utilized to guide the selection of appropriate HME processing temperature. In the currently studied copovidone-nifedipine system, a critical temperature, which is substantially lower (∼13 °C) than the melting point of crystalline API, was captured during a temperature ramp examination and regarded as the critical point at which the API could molecularly dissolve into the polymer. Based on the identification of this critical point, various solid dispersions were prepared by HME processing below, at, and above the critical temperature (both below and above the melting temperature (Tm) of crystalline API). In addition, the resultant extrudates along with two control solid dispersions prepared by physical mixing and cryogenic milling were assessed by X-ray diffraction, differential scanning calorimetry, hot stage microscopy, rheology, and solid-state NMR. Physicochemical properties of resultant solid dispersions indicated that the identified critical temperature is sufficient for the polymer-API system to reach a molecular-level mixing, manifested by the transparent and smooth appearance of extrudates, the absence of API crystalline diffraction and melting peaks, dramatically decreased rheological properties, and significantly improved polymer-API miscibility. Once the critical temperature has been achieved, further raising the processing temperature only results in limited improvement of API dispersion, reflected by slightly reduced storage modulus and complex viscosity and limited improvement in miscibility.

Assessing Mixing Quality of a Copovidone-TPGS Hot Melt Extrusion Process with Atomic Force Microscopy and Differential Scanning Calorimetry.

Atomic force microscopy (AFM) and modulated differential scanning calorimetry (mDSC) were used to evaluate the extent of mixing of a hot melt extrusion process for producing solid dispersions of copovidone and D-α-tocopherol polyethylene glycol 1000 succinate (TPGS 1000). In addition to composition, extrusion process parameters of screw speed and thermal quench rate were varied. The data indicated that for 10% TPGS and 300 rpm screw speed, the mixing was insufficient to yield a single-phase amorphous material. AFM images of the extrudate cross section for air-cooled material indicate round domains 200 to 700 nm in diameter without any observed alignment resulting from the extrusion whereas domains in extrudate subjected to chilled rolls were elliptical in shape with uniform orientation. Thermal analysis indicated that the domains were predominantly semi-crystalline TPGS. For 10% TPGS and 600 rpm screw speed, AFM and mDSC data were consistent with that of a single-phase amorphous material for both thermal quench rates examined. When the TPGS concentration was reduced to 5%, a single-phase amorphous material was achieved for all conditions even the slowest screw speed studied (150 rpm).

The impact of roller compaction and tablet compression on physicomechanical properties of pharmaceutical excipients.

Material properties play a significant role in pharmaceutical processing. The impact of roller compaction (RC) and tablet compression on solid fraction (SF), tensile strength (TS) and flexural modulus (FM) of Avicel DG [co-processed excipient with 75% microcrystalline cellulose (MCC) and 25% anhydrous dibasic calcium phosphate (DCPA)], lactose and 1:1 Mixture of the two was studied. Materials were roller compacted at different force and roller type and compressed into tablets over a range of compression pressures (CP). SF, TS and FM were determined for ribbons and tablets. Roller force was a significant variable affecting SF while roller type was not. Both SF and TS of tablets increased with CP with Avicel DG exhibiting greater TS than that of 1:1 Mixture while tablets of lactose had the lowest TS. The TS of tablets decreased exponentially with tablet porosity. Ribbon of Avicel DG had higher TS and lower SF than lactose and greater reworkability. This is attributed to plastic deformation of MCC resulting in high degree of bonding and fragmentation of DCPA that fills the void spaces during tablet compression. The lack of significant increase in SF and low tablet TS for lactose upon compression is likely due to its brittle fragmentation and some elastic recovery as shown by the high FM.

Continuous Twin-Screw wet granulation process with In-Barrel drying and NIR setup for Real-Time Moisture Monitoring.

The purpose of this study was to evaluate if wet granule formation and drying could take place in a single operation by utilizing in-barrel drying. The drying kinetics of the formulation were studied in order to select appropriate processing parameters and assess feasibility with short residence times in the extruder. The 18-mm extruder was operated in a 40:1 L:D ratio with 8 zones. The first two zones were used for material feeding and wet granule formation and the remaining zones were used for drying at elevated temperature. The impact of screw configuration as well as screw speed, feed rate, and residence time were all studied to optimize the drying process. Due to limitations of temperature and residence time, vacuum was added to enable sufficient drying. In-line NIR spectroscopy was incorporated into the twin-screw wet granulation (TSWG) process to monitor the moisture content of wet granules in real-time. The set-up was optimized and a predictive model was developed for future experiments. This study demonstrated the success of this technique on a pilot-scale (18-mm) extruder for the first time. Granules were formed and dried to a target loss on drying (LOD) of less than 2 % at moderate temperatures (100 °C - 110 °C) with one single operation. Streamlining wet granulation and drying into one unit operation can have a profound impact on pharmaceutical manufacturing reducing time, footprint, and environmental exposure due to reduced product transfers.

Pediatric Mini-Tablets: Predicting the Hidden Risk of Fill Errors.

Compressed mini-tablets in sachets or capsules are an increasingly prevalent oral solid dosage form for pediatric products. While resembling adult tablets, additional care is required to control weight and potency (blend uniformity) variation due to their small size (≤2.5 mm average diameter). Additionally, sachet fill count errors complicate dose accuracy as they are difficult to resolve with weight-checking equipment. This study quantified the probability of failing content uniformity (CU) specifications (which results in the inability to release a batch) defined in USP <905> using a Monte Carlo computational model. Failure risk was modeled as a function of sachet fill count, mini-tablet weight, potency distribution, and fill error frequency. The model allows product developers to (1) determine appropriate fill counts based on anticipated product weight and potency relative standard deviation (RSD), (2) set fill error probability tolerances for sachet filling processes, (3) identify CU improvement opportunities, and (4) quantify the probability of CU failure informing risk management activities and risk disclosure for regulatory agencies. A representative product with weight and potency RSD no greater than 5%, fill count of 1-4 mini-tablets per sachet, and fill error probability per mini-tablet filled of 0.1% may experience CU batch failure probabilities as high as 8.23%, but only 0.283% if the fill count is increased to 5-10 mini-tablets per sachet. Generally, fill counts of less than five mini-tablets per sachet should be avoided where possible.

Evaluation of Ceolus™ microcrystalline cellulose grades for the direct compression of enteric-coated pellets.

The preparation of multiparticulate tablets by direct compression of functionally coated pellets is technologically challenging. The objective was to investigate the influence of different grades of microcrystalline cellulose (Ceolus™ UF-711, PH-102, PH-200 and KG-802) as fillers on the properties of blends and tablets containing enteric pellets. Celphere™ spheres were drug-layered and then functionally coated with Eudragit(®) L 30 D-55/FS 30D dispersion. Tablets loaded with 50% pellets were prepared using pure or binary blends of microcrystalline cellulose fillers. The influence of the filler on the blend flow, segregation tendency, tablet hardness and enteric release properties were studied using a mixture design, and the optimum filler composition was determined. Rapidly disintegrating tablets, which yielded a drug release of less than 10% after 2 hours in acidic medium, could be successfully prepared. The blend composition had a significant effect on the flowability, but less on the tablet hardness which was influenced by the selection of lubricant. Blends containing celluloses with low bulk densities exhibited a reduced tendency to segregate. Pellet distribution uniformity was further improved when using Ceolus™ UF-711 blended with a high-density grade. As a conclusion, multiparticulate tablets containing enteric pellets with preserved delayed-release properties were successfully prepared using Ceolus™ microcrystalline celluloses as tableting excipients. The optimized filler blend for the direct compression of 50% enteric pellets into tablets contained Ceolus™ UF-711 as main component in combination with Ceolus™ PH-200.

Use of highly compressible Ceolus™ microcrystalline cellulose for improved dosage form properties containing a hydrophilic solid dispersion.

The development of amorphous solid dispersions containing poorly soluble drug substances has been well-documented; however, little attention has been given to the development of the finished dosage form. The objective of this study was to investigate the use of Ceolus(™) microcrystalline cellulose, a highly compressible excipient, for the production of rapidly disintegrating tablets containing a hydrophilic solid dispersion of a poorly soluble drug, indomethacin. Solid dispersions of indomethacin and Kollidon(®) VA64 were prepared by hot melt extrusion and characterized for amorphous nature. Milled dispersion particles at 500 mg/g drug loading were shown to be amorphous by differential scanning calorimetry and provided rapid dissolution in sink conditions. Physical characterization of the milled extrudate showed that the particle size of the intermediate was comparable with Ceolus(™) PH-102 and larger than the high compressibility grades of microcrystalline cellulose selected for the trial (Ceolus(™) KG-802, Ceolus(™) UF-711). Preliminary tableting trials showed that dissolution performance was significantly reduced for formulations at dispersion loadings in excess of 50%. Using a mixture design of experiments (DOE), the levels of PH-102, KG-802, UF-711, and PH-301 were optimized. Trials revealed a synergistic relationship between conventional grades (PH-102 and PH-301) and highly compressible grades (KG-802 and UF-711) leading to improved compression characteristics and more rapid dissolution rates. The formulation and resulting compressibility were also shown to have an impact on in vitro supersaturation indicating tablet formulation could impact oral bioavailability. Through the use of highly compressible microcrystalline cellulose grades such as Ceolus(™) KG-802 and UF-711, it may be possible to maximize the bioavailability benefit of amorphous solid dispersions administered as tablet dosage forms.

Flocculated amorphous itraconazole nanoparticles for enhanced in vitro supersaturation and in vivo bioavailability.

Rapid flocculation of nanoparticle dispersions of a poorly water soluble drug, itraconazole (Itz), was utilized to produce amorphous powders with desirable dissolution properties for high bioavailability in rats. Antisolvent precipitation (AP) was utilized to form Itz nanodispersions with high drug loadings stabilized with hydroxypropylmethylcellulose (HPMC) or the pH-sensitive Eudragit(®) L100-55 (EL10055). The HPMC dispersions were flocculated by desolvating the polymer through the addition of a divalent salt, and the enteric EL10055 by reducing the pH. The formation of open flocs by diffusion limited aggregation facilitated redispersion of the flocs at pH 6.8. Upon redispersion of the flocculated nanoparticles at pH 6.8, the particle size was modestly larger than the original size, on the order of 1 µm. High in vitro supersaturation (AUC) of the flocculated nanoparticle dispersions was observed in micellar media at pH 6.8, after 2 hours initial exposure at pH 1.2 to simulate the stomach, relative to the AUC for a commercially available Itz formulation, Sporanox. Greater in vivo bioavailability in rats was correlated directly to the higher in vitro AUC at pH 6.8 with micelles during the pH shift experiment for the flocculated nanoparticle dispersions relative to Sporanox. The ability to generate and sustain high supersaturation in micellar media at pH 6.8, as shown with the in vitro pH shift dissolution test, is beneficial for increasing bioavailability of Itz by oral delivery.

Solubilizing temperature of crystalline drug in polymer carrier: A rheological investigation on a posaconazole-copovidone system with low drug load.

Measuring the solubility of a crystalline active pharmaceutical ingredient (API) in a polymer-rich system is challenging due to the high viscosity of the polymer which kinetically impedes reaching the solubility equilibrium. In this study, a rheological approach of determining the solubilizing temperature of a crystalline API in a polymeric carrier has been developed. To validate the method, a model physical mixture of crystalline posaconazole and copovidone with a relatively low API load (25 wt%) was utilized. First, a comparison between conventional differential scanning calorimetry (DSC) and a rheological temperature ramp was conducted to illustrate that the rheological method could capture the melting point depression behavior similarly to the more well-known DSC technique. Second, to further understand the dissolution process of the crystalline posaconazole into the copovidone carrier and precisely measure the solubilizing temperature, a series of isothermal rheological time sweeps were carried out at various temperatures selected based on the rheological temperature sweep. Because the dissolved API molecule imparted a plasticizing effect to the polymeric carrier, the complex viscosity of the API-polymer system decreased gradually over time and correlated well to an exponential decay function. Moreover, dependent on the applied temperature, the API-polymer system eventually accomplished distinct equilibrium states (complex viscosities) within different time frames. The obtained time constants at different temperatures were fitted to the Arrhenius equation, allowing the determination of the activation energy of the mixing process. The results indicated that once the processing temperature exceeded a critical point below the melting point of the crystalline API, the API-polymer solubilization process switched from a surface dominated dispersive mechanism to a molecular-level solubilization mode, manifested by the significantly increased activation energy. To the best of our knowledge, the currently developed rheological approach was the first successful measurement of the solubilizing temperature of a crystalline drug in a polymer-rich system.

Insights into the Control of Drug Release from Complex Immediate Release Formulations.

The kinetics of water transport into tablets, and how it can be controlled by the formulation as well as the tablet microstructure, are of central importance in order to design and control the dissolution and drug release process, especially for immediate release tablets. This research employed terahertz pulsed imaging to measure the process of water penetrating through tablets using a flow cell. Tablets were prepared over a range of porosity between 10% to 20%. The formulations consist of two drugs (MK-8408: ruzasvir as a spray dried intermediate, and MK-3682: uprifosbuvir as a crystalline drug substance) and NaCl (0% to 20%) at varying levels of concentrations as well as other excipients. A power-law model is found to fit the liquid penetration exceptionally well (average R2>0.995). For each formulation, the rate of water penetration, extent of swelling and the USP dissolution rate were compared. A factorial analysis then revealed that the tablet porosity was the dominating factor for both liquid penetration and dissolution. NaCl more significantly influenced liquid penetration due to osmotic driving force as well as gelling suppression, but there appears to be little difference when NaCl loading in the formulation increases from 5% to 10%. The level of spray dried intermediate was observed to further limit the release of API in dissolution.

Production of advanced solid dispersions for enhanced bioavailability of itraconazole using KinetiSol Dispersing.

OBJECTIVES: To investigate the ability of KinetiSol Dispersing to prepare amorphous solid dispersions of itraconazole using concentration-enhancing polymers. METHODS: Concentration-enhancing nature of several cellulosic polymers (HPMC, hypromellose acetate succinate) was studied using a modified in vitro dissolution test. Solid dispersions were prepared by KinetiSol Dispersing and characterized for solid-state properties using X-ray diffraction and differential scanning calorimetry. Potency and release characteristics were also assessed by high-performance liquid chromatography. Oral bioavailability of lead formulations was also assessed in animal models. RESULTS: Screening studies demonstrated superior concentration-enhancing performance from the hypromellose acetate succinate polymer class. Data showed that stabilization was related to molecular weight and the degree of hydrophobic substitution on the polymer such that HF > MF approximately LF, indicating that stabilization was achieved through a combination of steric hindrance and hydrophobic interaction, supplemented by the amphiphilic nature and ionization state of the polymer. Solid dispersions exhibited amorphous solid-state behavior and provided neutral media supersaturation using a surfactant-free pH change method. Rank-order behavior was such that LF > MF > HF. Addition of Carbopol 974P increased acidic media dissolution, while providing a lower magnitude of supersaturation in neutral media because of swelling of the high viscosity gel. In vivo results for both lead compositions displayed erratic absorption was attributed to the variability of gastrointestinal pH in the animals. CONCLUSIONS: These results showed that production of amorphous solid dispersions containing concentration-enhancing polymers through KinetiSol Dispersing can provide improved oral bioavailability; however, additional formulation techniques must be developed to minimize variability associated with natural variations in subject gastrointestinal physiology.

Dissolution enhancement of a drug exhibiting thermal and acidic decomposition characteristics by fusion processing: a comparative study of hot melt extrusion and KinetiSol dispersing.

In this study, hot melt extrusion (HME) and KinetiSol Dispersing (KSD) were utilized to prepare dissolution-enhanced solid dispersions of Roche Research Compound A (ROA), a BCS class II drug. Preformulation characterization studies showed that ROA was chemically unstable at elevated temperatures and acidic pH values. Eudragit L100-55 and AQOAT LF (HPMCAS) were evaluated as carrier polymers. Dispersions were characterized for ROA recovery, crystallinity, homogeneity, and non-sink dissolution. Eudragit L100-55 dispersions prepared by HME required the use of micronized ROA and reduced residence times in order to become substantially amorphous. Compositions containing HPMCAS were also prepared by HME, but an amorphous dispersion could not be obtained. All HME compositions contained ROA-related impurities. KSD was investigated as a method to reduce the decomposition of ROA while rendering compositions amorphous. Substantially amorphous, plasticizer free compositions were processed successfully by KSD with significantly higher ROA recovery values and amorphous character than those achieved by HME. A near-infrared chemical imaging analysis was conducted on the solid dispersions as a measure of homogeneity. A statistical analysis showed similar levels of homogeneity in compositions containing Eudragit L100-55, while differences were observed in those containing HMPCAS. Non-sink dissolution analysis of all compositions showed rapid supersaturation after pH adjustment to approximately two to three times the equilibrium solubility of ROA, which was maintained for at least 24 h. The results of the study demonstrated that KSD is an effective method of forming dissolution-enhanced amorphous solid solutions in cases where HME is not a feasible technique.

CNS disorders--current treatment options and the prospects for advanced therapies.

The development of new pharmaceutical products has successfully addressed a multitude of disease states; however, new product development for treating disorders of the central nervous system (CNS) has lagged behind other therapeutic areas. This is due to several factors including the complexity of the diseases and the lack of technologies for delivery through the blood-brain barrier (BBB). This article examines the current state of six major CNS disease states: depression, epilepsy, multiple sclerosis (MS), neurodegenerative diseases (specifically Alzheimer's disease [AD]), neuropathic pain, and schizophrenia. Discussion topics include analysis of the biological mechanisms underlying each disease, currently approved products, and available animal models for development of new therapeutic agents. Analysis of currently approved therapies shows that all products depend on the molecular properties of the drug or prodrug to penetrate the BBB. Novel technologies, capable of enhancing BBB permeation, are also discussed relative to improving CNS therapies for these disease states.

Enhanced in vivo absorption of itraconazole via stabilization of supersaturation following acidic-to-neutral pH transition.

Previous attempts to improve the dissolution and absorption properties of itraconazole (ITZ) through advanced formulation design have focused only on release in acidic media; however, recent reports indicate that absorption occurs primarily in the proximal small intestine. This suggests that enhancing supersaturation of ITZ in neutral aqueous environments is essential for improving absorption. The aim of this study was to evaluate different polymeric stabilizers with either immediate release (IR) (Methocel E5, Methocel E50, Kollidon 12, and Kollidon 90) or enteric release (EUDRAGIT L 100-55, HP-55, and HP-55S) properties to determine the chemical and physical attributes of the polymeric stabilizers that promote supersaturation of ITZ in neutral media. Each amorphous composition was produced by hot-melt extrusion and characterized by differential scanning calorimetry. Dissolution testing by a supersaturated acidic-to-neutral pH change method was conducted on each composition. Testing of IR compositions revealed that Methocel was a superior stabilizer compared with Kollidon owing to stronger intermolecular interaction with ITZ molecules in solution. Increasing the molecular weight of polymers was found to promote ITZ supersaturation and was most likely attributable to increased solution viscosity resulting in retention of ITZ molecules in an enthalpically favored association with the polymer for extended durations. Of the enteric polymeric stabilizers, EUDRAGIT L 100-55 was found to be superior to both HP-55 grades because of its greater permeability to acid that allowed for improved hydration of ITZ in the acid phase as well as a greater number of free hydroxyl groups on the polymer backbone that presumably helped to stabilize ITZ in solution. The Methoceltrade mark E50 and EUDRAGIT L 100-55 formulations were evaluated for in vivo drug absorption in male Sprague-Dawley rats and were found to produce a threefold greater ITZ absorption over our previously reported IR formulations. The results of this study confirmed the hypothesis that supersaturation of ITZ following an acidic-to-neutral pH transition in vitro correlates directly to in vivo absorption.

Control Strategies for Drug Product Continuous Direct Compression-State of Control, Product Collection Strategies, and Startup/Shutdown Operations for the Production of Clinical Trial Materials and Commercial Products.

Continuous manufacturing (CM) has emerged in the pharmaceutical industry as a paradigm shift with significant advantages related to cost, efficiency, flexibility, and higher assurance of quality. The inherent differences from batch processes justify examining the CM control strategy more holistically. This article describes the current thinking for the control and implementation of CM, using the example of a direct compression process and taking into consideration the ICH Q10 definition of "state of control" and process validation requirements. Statistical process control using control charts, sources of variation, process capability, and process performance is explained as a useful concept that can help assess the impact of variation within a batch and indicates if a process is in state of control. The potential for time-variant nature of startup and shutdown with CM is discussed to assure product quality while minimizing waste as well as different options for detection and isolation of non-conforming materials due to process upsets. While different levels of control are possible with CM, an appropriate balance between process control and end product testing is needed depending on the level of process understanding at the different stages of development from the production of clinical supplies through commercialization.

Investigation of process temperature and screw speed on properties of a pharmaceutical solid dispersion using corotating and counter-rotating twin-screw extruders.

OBJECTIVE: The use of corotating twin screw hot-melt extruders to prepare amorphous drug/polymer systems has become commonplace. As small molecule drug candidates exiting discovery pipelines trend towards higher MW and become more structurally complicated, the acceptable operating space shifts below the drug melting point. The objective of this research is to investigate the extrusion process space, which should be selected to ensure that the drug is solubilized in the polymer with minimal thermal exposure, is critical in ensuring the performance, stability and purity of the solid dispersion. METHODS: The properties of a model solid dispersion were investigated using both corotating and counter-rotating hot-melt twin-screw extruders operated at various temperatures and screw speeds. The solid state and dissolution performance of the resulting solid dispersions was investigated and evaluated in context of thermodynamic predictions from Flory-Huggins Theory. In addition, the residence time distributions were measured using a tracer, modelled and characterized. KEY FINDINGS: The amorphous content in the resulting solid dispersions was dependent on the combination of screw speed, temperature and operating mode. CONCLUSIONS: The counter-rotating extruder was observed to form amorphous solid dispersions at a slightly lower temperature and with a narrower residence time distribution, which also exhibited a more desirable shape.

Dry powder coating of pharmaceuticals: a review.

Over the last half century, film coating technology has evolved significantly in terms of compositions and manufacturing processes, allowing for greater functionality, flexibility and efficiency. Driven by a combination of cost considerations and functionality, a range of dry powder coating technologies have been developed in both academic and industrial settings. These technologies can be generally classified into three major types based on the layer formation process: liquid assisted, thermal adhesion and electrostatic. In addition to specific manufacturing processes that must be implemented to achieve the desired product attributes, many of these techniques also require the use of novel excipients and specific formulations to provide acceptable manufacturability. This review summarizes the current dry powder coating technologies and highlights their industrial applicability with publicly disclosed case studies. Commentary on the future directions of dry powder coating is also provided.