Understanding Poor Milling Behavior of Voriconazole from Crystal Structure and Intermolecular Interactions.

The study investigated the milling behavior of voriconazole (VRZ) subjected to particle size reduction using air jet mill at differential air pressures of 5, 6, 7, and 8 bar for five cycles at each pressure. The crystal structure of VRZ was probed for understanding the fracture behavior from crystal packing and intermolecular interactions using molecular modeling tools of attachment energy (Eatt), density functional theory, and energy framework analysis. Upon milling for different cycles, VRZ showed that size reduction from (D90) 20 to 9 µm and 100% particles could not be milled to sizes below 9 µm, with the increase in either the milling intensity or cycle. The milled samples retained the original crystal lattice as evident from consistent melting endotherm (Tm = 130.75 °C); heat of fusion (ΔHf = 96.52 J/g) values; and the plate-shaped morphology. The powder X-ray diffraction pattern of milled samples consistently showed characteristic peaks of stable form B of VRZ. The crystallographic plane (001) was found to be the most prominent slip and the cleavage plane due to least Eatt and weak noncovalent interactions (6.996 kJ/mol) between 3'H and 4'F functional groups of the neighboring planes. The predicted indentation hardness value of 228.67 MPa further indicated toward the plastic nature of VRZ crystals. Corroborating outcomes from the different molecular modeling tools for VRZ, cleavage along the plane (001) was determined to be energetically favorable, whereas cleavage of isotropic 2D molecular sheets was energetically unfavorable. As milling proceeds and crystal reduces in size, contact surface area and overall interaction energy decrease contributing to plastic behavior of the crystal. It was concluded that crystal plasticity and isotropic 2D molecular sheets along with the orientation of particles to the direction of stress and attrition energy during air jet milling are contributing factors for nonuniform size reduction of VRZ particles.

Role of surface molecular environment and amorphous content in moisture sorption behavior of milled Terbutaline Sulphate.

Milling may cause undesired changes in crystal topology, due to exposure of new facets, their corresponding functional groups and surface amorphization. This study investigated effect of milling induced surface amorphous content and chemical environment on moisture sorption behavior of a model hydrophilic drug, Terbutaline Sulphate (TBS). A Dynamic Vapor Sorption (DVS) based analytical method was developed to detect amorphous content, with LOD and LOQ of 0.41% and 1.24%w/w, respectively. The calibration curve gave a linear regression of 0.999 in a concentration range of 0-16.36%w/w amorphous content plotted against surface area normalized % weight change, due to moisture sorption. TBS was milled using air jet mill at 8 Bars for 3 cycles (D90- 3.46µm) and analyzed using the validated DVS method prior to and post conditioning. The moisture sorption was higher in case of milled unconditioned TBS. Molecular Dynamics Simulation (MDS) was performed to identify the cause for increased moisture sorption due to altered surface environment or amorphous content. The results implied that the new planes and functional groups exposed on milling had negligible contribution to moisture sorption and the higher moisture sorption in milled unconditioned TBS was due to surface amorphization. Conditioning under elevated humidity recrystallized the milling-induced surface amorphous content and led to decreased moisture sorption in milled conditioned TBS.

The Role of Cocrystallization-Mediated Altered Crystallographic Properties on the Tabletability of Rivaroxaban and Malonic Acid.

The present work aims to understand the crystallographic basis of the mechanical behavior of rivaroxaban-malonic acid cocrystal (RIV-MAL Co) in comparison to its parent constituents, i.e., rivaroxaban (RIV) and malonic acid (MAL). The mechanical behavior was evaluated at the bulk level by performing "out of die" bulk compaction and at the particle level by nanoindentation. The tabletability order for the three solids was MAL < RIV < RIV-MAL Co. MAL demonstrated "lower" tabletability because of its lower plasticity, despite it having reasonably good bonding strength (BS). The absence of a slip plane and "intermediate" BS contributed to this behavior. The "intermediate" tabletability of RIV was primarily attributed to the differential surface topologies of the slip planes. The presence of a primary slip plane (0 1 1) with flat-layered topology can favor the plastic deformation of RIV, whereas the corrugated topology of secondary slip planes (1 0 ) could adversely affect the plasticity. In addition, the higher elastic recovery of RIV crystal also contributed to its tabletability. The significantly "higher" tabletability of RIV-MAL Co among the three molecular solids was the result of its higher plasticity and BS. Flat-layered topology slip across the (0 0 1) plane, the higher degree of intermolecular interactions, and the larger separation between adjacent crystallographic layers contributed to improved mechanical behavior of RIV-MAL Co. Interestingly, a particle level deformation parameter H/E (i.e., ratio of mechanical hardness H to elastic modulus E) was found to inversely correlate with a bulk level deformation parameter σ0 (i.e., tensile strength at zero porosity). The present study highlighted the role of cocrystal crystallographic properties in improving the tabletability of materials.

Elucidating Molecular- and Particle-Level Changes during the Annealing of a Micronized Crystalline Drug.

Micronization of crystalline active pharmaceutical ingredients can lead to formation of a thermodynamically unstable material with surface disorder. This material undergoes structural stabilization and particle-level changes over time that, in turn, alters the surface properties and interparticle interactions of the micronized drug. The unstable nature of the micronized drug can lead to variability in the performance of dry powder inhaler drug products. To improve the physicochemical stability of the micronized drug, an annealing step is often introduced. However, there is limited understanding of changes in the micronized drug under different annealing conditions. In this study, we examine the molecular- and particle-level changes occurring in a micronized drug during annealing under varying temperature and humidity conditions using orthogonal techniques. We demonstrate the use of surface free energy (SFE) measured by inverse gas chromatography (IGC) to monitor surface-specific changes. Micronization led to an increase in SFE, which progressively reduced during annealing. SFE trends correlated with the molecular-level surface disorder patterns measured by relative humidity perfusion microcalorimetry. The interparticle interactions tracked using IGC and atomic force microscopy show that as the micronized drug stabilized, there was a transition from dominant drug-drug cohesive forces to drug-lactose adhesive forces. For the nonhygroscopic model compound, combined high temperature-high humidity conditions showed fastest annealing kinetics. Further, the SFE descriptor enabled us to differentiate the extent of mechanical activation of the neat micronized drug and co-micronized drug-magnesium stearate blends. The study identifies tools for characterizing postmicronization material changes that can help develop materials with consistent quality.

Correlations between surface composition and aerosolization of jet-milled dry powder inhaler formulations with pharmaceutical lubricants.

Co-jet-milling drugs and lubricants may enable simultaneous particle size reduction and surface coating to achieve satisfactory aerosolization performance. This study aims to establish the relationship between surface lubricant coverage and aerosolization behavior of a model drug (ciprofloxacin HCl) co-jet-milled with lubricants [magnesium stearate (MgSt) or l-leucine]. The co-jet-milled formulations were characterized for particle size, morphology, cohesion, Carr's index, and aerosolization performance. The surface lubricant coating was assessed by probing surface chemical composition using X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary-ion mass spectrometry (ToF-SIMS). The effects of co-jet-milling on the surface energy and in vitro dissolution of ciprofloxacin were also evaluated. Our results indicated that, in general, the ciprofloxacin co-jet-milled with l-leucine at >0.5% w/w showed a significant higher fine particle fraction (FPF) compared with the ciprofloxacin jet-milled alone. The FPF values plateau at or above 5% w/w for both MgSt and l-leucine. We have established the quantitative correlations between surface lubricant coverage and aerosolization in the tested range for each of the lubricants. More importantly, our results suggest different mechanisms to improve aerosolization for MgSt-coating and l-leucine-coating, respectively: MgSt-coating reduces inter-particulate interactions through the formation of low surface energy coating films, while l-leucine-coating not only reduces the surface energy but also creates rough particle surfaces that reduce inter-particulate contact area. Furthermore, surface coatings with 5% w/w MgSt (which is hydrophobic) did not lead to substantial changes in in vitro dissolution. Our findings have shown that the coating structure/quality and their effects could be highly dependent on the process and the coating material. The findings from this mechanistic study provide fundamental understanding of the critical effects of MgSt and l-leucine surface coverages on aerosolization and powder flow properties of inhalation particles.

Continuous Twin Screw Wet Granulation and Drying-Control Strategy for Drug Product Manufacturing.

The use of continuous manufacturing has been increasing within the pharmaceutical industry over the last few years. Continuous direct compression has been the focus of publications on the topic to date. The use of wet granulation can improve segregation resistance, uniformity, enhance density, and flow properties for improved tabletability, or improve stability of products that cannot be manufactured by using a direction compression process. This article focuses on development of appropriate control strategies for continuous wet granulation (especially twin screw wet granulation) through equipment design, material properties and manufacturing process along with areas where additional understanding is required. The article also discusses the use of process analytical technologies as part of the control and automation approach to ensure a higher assurance of product quality. Increased understanding of continuous wet granulation should result in increased utilization of the technique, thereby allowing for an increase in diversity of products manufactured by continuous manufacturing and the benefits that comes with a more complex process such as wet granulation compared with direct compression process.

Demonstration of pharmaceutical tablet coating process by injection molding technology.

We demonstrate the coating of tablets using an injection molding (IM) process that has advantage of being solvent free and can provide precision coat features. The selected core tablets comprising 10% w/w griseofulvin were prepared by an integrated hot melt extrusion-injection molding (HME-IM) process. Coating trials were conducted on a vertical injection mold machine. Polyethylene glycol and polyethylene oxide based hot melt extruded coat compositions were used. Tablet coating process feasibility was successfully demonstrated using different coating mold designs (with both overlapping and non-overlapping coatings at the weld) and coat thicknesses of 150 and 300 µm. The resultant coated tablets had acceptable appearance, seal at the weld, and immediate drug release profile (with an acceptable lag time). Since IM is a continuous process, this study opens opportunities to develop HME-IM continuous processes for transforming powder to coated tablets.

Tablet coating by injection molding technology - Optimization of coating formulation attributes and coating process parameters.

We developed and evaluated a solvent-free injection molding (IM) coating technology that could be suitable for continuous manufacturing via incorporation with IM tableting. Coating formulations (coating polymers and plasticizers) were prepared using hot-melt extrusion and screened via stress-strain analysis employing a universal testing machine. Selected coating formulations were studied for their melt flow characteristics. Tablets were coated using a vertical injection molding unit. Process parameters like softening temperature, injection pressure, and cooling temperature played a very important role in IM coating processing. IM coating employing polyethylene oxide (PEO) based formulations required sufficient room humidity (>30% RH) to avoid immediate cracks, whereas other formulations were insensitive to the room humidity. Tested formulations based on Eudrajit E PO and Kollicoat IR had unsuitable mechanical properties. Three coating formulations based on hydroxypropyl pea starch, PEO 1,000,000 and Opadry had favorable mechanical (<700MPa Young's modulus, >35% elongation, >95×104J/m3 toughness) and melt flow (>0.4g/min) characteristics, that rendered acceptable IM coats. These three formulations increased the dissolution time by 10, 15 and 35min, respectively (75% drug release), compared to the uncoated tablets (15min). Coated tablets stored in several environmental conditions remained stable to cracking for the evaluated 8-week time period.

Integrated hot-melt extrusion - injection molding continuous tablet manufacturing platform: Effects of critical process parameters and formulation attributes on product robustness and dimensional stability.

This study provides a framework for robust tablet development using an integrated hot-melt extrusion-injection molding (IM) continuous manufacturing platform. Griseofulvin, maltodextrin, xylitol and lactose were employed as drug, carrier, plasticizer and reinforcing agent respectively. A pre-blended drug-excipient mixture was fed from a loss-in-weight feeder to a twin-screw extruder. The extrudate was subsequently injected directly into the integrated IM unit and molded into tablets. Tablets were stored in different storage conditions up to 20 weeks to monitor physical stability and were evaluated by polarized light microscopy, DSC, SEM, XRD and dissolution analysis. Optimized injection pressure provided robust tablet formulations. Tablets manufactured at low and high injection pressures exhibited the flaws of sink marks and flashing respectively. Higher solidification temperature during IM process reduced the thermal induced residual stress and prevented chipping and cracking issues. Polarized light microscopy revealed a homogeneous dispersion of crystalline griseofulvin in an amorphous matrix. DSC underpinned the effect of high tablet residual moisture on maltodextrin-xylitol phase separation that resulted in dimensional instability. Tablets with low residual moisture demonstrated long term dimensional stability. This study serves as a model for IM tablet formulations for mechanistic understanding of critical process parameters and formulation attributes required for optimal product performance.

Development of Maltodextrin-Based Immediate-Release Tablets Using an Integrated Twin-Screw Hot-Melt Extrusion and Injection-Molding Continuous Manufacturing Process.

The combination of hot-melt extrusion and injection molding (HME-IM) is a promising process technology for continuous manufacturing of tablets. However, there has been limited research on its application to formulate crystalline drug-containing immediate-release tablets. Furthermore, studies that have applied the HME-IM process to molded tablets have used a noncontinuous 2-step approach. The present study develops maltodextrin (MDX)-based extrusion-molded immediate-release tablets for a crystalline drug (griseofulvin) using an integrated twin-screw HME-IM continuous process. At 10% w/w drug loading, MDX was selected as the tablet matrix former based on a preliminary screen. Furthermore, liquid and solid polyols were evaluated for melt processing of MDX and for impact on tablet performance. Smooth-surfaced tablets, comprising crystalline griseofulvin solid suspension in the amorphous MDX-xylitol matrix, were produced by a continuous process on a twin-screw extruder coupled to a horizontally opening IM machine. Real-time HME process profiles were used to develop automated HME-IM cycles. Formulation adjustments overcame process challenges and improved tablet strength. The developed MDX tablets exhibited adequate strength and a fast-dissolving matrix (85% drug release in 20 min), and maintained performance on accelerated stability conditions.

Effect of different "states" of sorbed water on amorphous celecoxib.

Glass transition temperature (Tg) of an amorphous drug is a vital physical phenomenon that influences its visco-elastic properties, physical, and chemical stability. Water acts as a plasticizer for amorphous drugs thus increasing their recrystallization kinetics. This reduces the solubility advantage of an amorphous drug. Hence, there is an interest in understanding the relationship between water content and Tg of amorphous drug. We have studied the effect of "state" of sorbed water on Tg of amorphous celecoxib (ACLB). ACLB was allowed to sorb water at relative humidity of 33%, 53%, 75%, and 93%. ALCB showed biphasic sorption of water designated as "bound" and "solvent-like" state of water associated with ACLB. Molecular modeling studies provided deeper insights into the interaction of water with ACLB. A distinct co-relationship between the state of water and its plasticization capacity was observed. Bound state of water had a very profound effect on the fall in experimentally observed Tg (T(g-exp)) value. Solvent-like state of water had little impact on T(g-exp) value. Tg of ACLB-water mixture was predicted by Gordon-Taylor equation (T(g-pre)). The deviations in T(g-exp) and Tg-pre were correlated to volume non-additivity and non-ideal mixing. This study has implications on the development of formulations based on amorphous forms.

Solubility advantage from amorphous etoricoxib solid dispersions.

OBJECTIVE: This study aimed to evaluate kinetic solubility advantage of amorphous etoricoxib solid dispersions prepared with three water soluble polymers and correlate it with solid state and supersaturated drug solution stabilization potential of these polymers. METHODS: Amorphous solid dispersions (ASDs) of etoricoxib were prepared with polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP) and hydroxyethyl cellulose (HEC) at 70:30w/w ratio and characterized for glass transition temperature (Tg), miscibility and intermolecular interactions. Kinetic solubility profiles of amorphous etoricoxib and its ASDs were determined in water at 37 °C. Solid-state stability was assessed by enthalpy relaxation studies at a common degree of undercooling of around 19.0 °C at 0% RH. Recrystallization behavior of supersaturated drug solution was evaluated in the absence and presence of pre-dissolved polymer at 37 °C. RESULTS: Amorphous etoricoxib exhibited rapid solid-to-solid transition to yield a solubility advantage of merely 1.5-fold in water. Among the ASDs, etoricoxib-PVP dispersion exhibited maximal "peak" (2-fold) and "plateau" (1.8-fold) solubility enhancement, while etoricoxib-PVA dispersion could only sustain the "peak" solubility achieved by amorphous etoricoxib. In contrast, etoricoxib-HEC dispersion displayed no solubility advantage. The rank order for solid state and supersaturated solution stabilization followed a similar trend of amorphous etoricoxib < HEC < PVA < PVP. CONCLUSION: Dissolution behavior of ASDs is influenced by concomitantly occurring solid phase changes, thus understanding these processes independently can enable assessment of the predominant route of drug crystallization and stabilization by the polymer.

Barrier coated drug layered particles for enhanced performance of amorphous solid dispersion dosage form.

Amorphous solid dispersions (ASDs) may entail tailor-made dosage form design to exploit their solubility advantage. Surface phenomena dominated the performance of amorphous celecoxib solid dispersion (ACSD) comprising of amorphous celecoxib (A-CLB), polyvinylpyrrolidone, and meglumine (7:2:1, w/w). ACSD cohesive interfacial interactions hindered its capsule dosage form dissolution (Puri V, Dhantuluri AK, Bansal AK 2011. J Pharm Sci 100:2460-2468). Furthermore, ACSD underwent significant devitrification under environmental stress. In the present study, enthalpy relaxation studies revealed its free surface to contribute to molecular mobility. Based on all these observations, barrier coated amorphous CLB solid dispersion layered particles (ADLP) were developed by Wurster process, using microcrystalline cellulose as substrate and polyvinyl alcohol (PVA), inulin, and polyvinyl acetate phthalate (PVAP) as coating excipients. Capsule formulations of barrier coated-ADLP could achieve rapid dispersibility and high drug release. Evaluation under varying temperature and RH conditions suggested the crystallization inhibitory efficiency in order of inulin < PVA ≈ PVAP; however, under only temperature treatment, crystallization inhibition increased with increase in T(g) of the coating material. Simulated studies using DSC evidenced drug-polymer mixing at the interface as a potential mechanism for surface stabilization. In conclusion, surface modification yielded a fast dispersing robust high drug load ASD based dosage form.

Effect of counterions on the properties of amorphous atorvastatin salts.

Amorphous systems have gained importance as a tool for addressing delivery challenges of poorly water soluble drugs. A careful assessment of thermodynamic and kinetic behavior of amorphous form is necessary for successful use of amorphous form in drug delivery. The present study was undertaken to evaluate effect of monovalent sodium (Na(+); ATV Na), and bivalent calcium (Ca(2+); ATV Ca) and magnesium (Mg(2+); ATV Mg) counterions on properties of amorphous salts of atorvastatin (ATV) model drug. Amorphous form was generated from crystalline salts of ATV by spray drying, and characterized for glass transition temperature (T(g)), fragility and devitrification tendency. In addition, chemical stability of the amorphous salt forms was evaluated. Fragility was studied by calculating activation enthalpy for structural relaxation at T(g), from heating rate dependency of T(g). Density functional theory and relative pK(a)'s of counterions were evaluated to substantiate trend in glass transition temperature. T(g) of salts followed order: ATV Ca>ATV Mg>ATV Na. All salts were fragile to moderately fragile, with D value ranging between 9 and 16. Ease of devitrification followed the order: ATV Na∼ATV Mg≫ATV Ca, using isothermal crystallization and reduced crystallization temperature method. Chemical stability at 80°C showed higher degradation of amorphous ATV Ca (∼5%), while ATV Na and ATV Mg showed degradation of 1-2%. Overall, ATV Ca was better in terms of glass forming ability, higher T(g) and physical stability. The study has importance in selection of a suitable amorphous form, during early drug development phase.

Role of α-relaxation on crystallization of amorphous celecoxib above T(g) probed by dielectric spectroscopy.

In the present study, the role of α-relaxation toward isothermal crystallization of amorphous celecoxib was studied using dielectric spectroscopy (DES). The dielectric response of the α-relaxation was measured as a function of frequency (10⁻¹ to 106 Hz), isothermally at every 4 K interval in the range of 303.15 to 443.15 K. The dielectric loss spectrum at each temperature was analyzed using the Havriliak Negami (HN) equation to extract the characteristic relaxation time, τ(HN). Two Vogel-Fulcher-Tammann (VFT) functions were required for representing the temperature dependence of τ(HN) across the temperature range of study. The VFT fit parameters obtained from the two regions varied drastically pointing toward the underlying differences in the dynamics of relaxation above and below the crossover. Later, in situ isothermal crystallization experiments were performed at 363.15, 368.15, 373.15, and 378.15 K. The conversion rate, obtained from the normalized dielectric strength, was modeled using the Avrami model, which indicated the possibility of different crystallization mechanism at higher crystallization temperatures. HN shape parameters, α(HN) and product of α(HN) and ß(HN), were analyzed during the course of crystallization to understand the dynamics of amorphous phase when crystallites were being evolved. HN shape parameters indicated α-like motions were affected, whereas ß-like remained unaffected by the crystallization temperature. Characteristic crystallization time, τ(cr), obtained from Avrami fits, showed Arrhenius type of temperature dependence (R² = 0.999). A plot between log τ(cr) and log τ(HN) show a linear regression with R² of 0.997 indicating the direct correlation between these two phenomena. However, the coupling coefficient was found to be varying within the temperature range of study, indicating tendency of crystallization to be more diffusion controlled at higher crystallization temperatures. With different crystalline solid phase crystallizing at higher crystallization temperature, complemented with direct correlation between log τ(cr) and log τ(HN), Avrami modeling of crystallization and HN shape parameter analysis, the role of α-relaxation in the crystallization of amorphous celecoxib at T > T(g) is emphasized.

Investigation of atypical dissolution behavior of an encapsulated amorphous solid dispersion.

Poor dissolution performance is one of the challenges encountered in dosage form design of amorphous solid dispersions (ASDs). This study was aimed to investigate the effect of solid-liquid interactions of an encapsulated ASD on drug release. Drug release profiles of a molecularly interacting amorphous celecoxib solid dispersion (ACSD) comprising of amorphous celecoxib (A-CLB), polyvinylpyrrolidone (PVP), and meglumine (7:2:1, w/w) were compared with crystalline CLB (C-CLB), in powder and capsule form. Although, ACSD powder displayed 28- to 50-fold higher dissolution efficiency at 60 min (DE(60)), the DE(60) in the encapsulated state were drastically reduced due to the formation of a nondispersible plug. The accompanied physical and compositional changes were investigated using X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, and chromatographic techniques. ACSD displayed optimal wettability, sustained A-CLB-PVP interactions, and suppressed phase transformations in aqueous media. Furthermore, Fourier transform infrared and texture analysis revealed role of intermolecular interactions of the solid dispersion, which (i) altered PVP's functionality and (ii) promoted interparticle cohesivity via water-mediated hydrogen bonds, resulting in solid mass agglomeration. Parallel evaluation of A-CLB, physical mixture of ACSD components, and C-CLB solid dispersion supported the above inferences. On the basis of these findings, rationalized formulation approaches for ASD-based drug products are discussed.

Wettability and surface chemistry of crystalline and amorphous forms of a poorly water soluble drug.

The present study compares energetics of wetting behavior of crystalline and amorphous forms of a poorly water soluble drug, celecoxib (CLB) and attempts to correlate it to their surface molecular environment. Wettability and surface free energy were determined using sessile drop contact angle technique and water vapor sorption energetics was measured by adsorption calorimetry. The surface chemistry was elucidated by X-ray photoelectron spectroscopy (XPS) and crystallographic evaluation. The two solid forms displayed distinctly different wetting with various probe liquids and in vitro dissolution media. The crystalline form surface primarily exhibited dispersive surface energy (47.3mJ/m(2)), while the amorphous form had a slightly reduced dispersive (45.2mJ/m(2)) and a small additional polar (4.8mJ/m(2)) surface energy. Calorimetric measurements, revealed the amorphous form to possess a noticeably high differential heat of absorption, suggesting hydrogen bond interactions between its polar energetic sites and water molecules. Conversely, the crystalline CLB form was found to be inert to water vapor sorption. The relatively higher surface polarity of the amorphous form could be linked to its greater oxygen-to-fluorine surface concentration ratio of 1.27 (cf. 0.62 for crystalline CLB), as determined by XPS. The crystallographic studies of the preferred cleavage plane (020) of crystalline CLB further supported its higher hydrophobicity. In conclusion, the crystalline and amorphous forms of CLB exhibited disparate surface milieu, which in turn can have implications on the surface mediated events.

Solid state characterization of commercial crystalline and amorphous atorvastatin calcium samples.

Atorvastatin calcium (ATC), an anti-lipid BCS class II drug, is marketed in crystalline and amorphous solid forms. The objective of this study was to perform solid state characterization of commercial crystalline and amorphous ATC drug samples available in the Indian market. Six samples each of crystalline and amorphous ATC were characterized using X-ray powder diffractometry (XRPD), differential scanning calorimetry (DSC), thermogravimetric analysis, Karl Fisher titrimetry, microscopy (hot stage microscopy, scanning electron microscopy), contact angle, and intrinsic dissolution rate (IDR). All crystalline ATC samples were found to be stable form I, however one sample possessed polymorphic impurity, evidenced in XRPD and DSC analysis. Amongst the amorphous ATC samples, XRPD demonstrated five samples to be amorphous 'form 27', while, one matched amorphous 'form 23'. Thermal behavior of amorphous ATC samples was compared to amorphous ATC generated by melt quenching in DSC. ATC was found to be an excellent glass former with T(g)/T(m) of 0.95. Residual crystallinity was detected in two of the amorphous samples by complementary use of conventional and modulated DSC techniques. The wettability and IDR of all amorphous samples was found to be higher than the crystalline samples. In conclusion, commercial ATC samples exhibited diverse solid state behavior that can impact the performance and stability of the dosage forms.

Trends in pharmaceutical taste masking technologies: a patent review.

According to the year 2003 survey of pediatricians by the American Association of Pediatrics, unpleasant taste was the biggest barrier for completing treatment in pediatrics. The field of taste masking of active pharmaceutical ingredients (API) has been continuously evolving with varied technologies and new excipients. The article reviews the trends in taste masking technologies by studying the current state of the art patent database for the span of year 1997 to 2007. The worldwide database of European patent office (http://ep.espacenet.com) was employed to collect the patents and patent applications. It also discusses the possible reasons for the change of preferences in the taste masking technologies with time. The prime factors critical to the selection of an optimal taste masking technique such as the extent of drug bitterness, solubility, particle characteristics, dosage form and dose are briefly discussed.