The development of novel excipients with enhanced functionality has been explored using particle engineering by co-processing. The aim of this study was to improve the functionality of tapioca starch (TS) for direct compression by co-processing with gelatin (GEL) and colloidal silicon dioxide (CSD) in optimized proportions. Design of Experiment (DoE) was employed to optimize the composition of the co-processed excipient using the desirability function and other supporting studies as a basis for selecting the optimized formulation. The co-processed excipient (SGS) was thereafter developed by the method of co-fusion. Flow and compaction studies of SGS were carried out in comparison to its parent component (TS) and physical mixture (SGS-PM). Tablets were prepared by direct compression (DC) containing ibuprofen (200 mg) as a model for poor compressibility using SGS, Prosolv®, and StarLac® as multifunctional excipients. The optimized composition of SGS corresponded to TS (90%), GEL (7.5%), and CSD (2.5%). The functionality of SGS was improved relative to SGS-PM in terms of flow and compression. Tablets produced with SGS were satisfactory and conformed to USP specifications for acceptable tablets. SGS performed better than Prosolv® in terms of disintegration and was superior to StarLac with respect to tensile strength and disintegration time. The application of DoE was successful in optimizing and developing a starch-based co-processed excipient that can be considered for direct compression tableting.

philic' (100) crystals adsorbed more moisture than 'phobic' (001) crystals which translated into higher degradation of 'philic' (100) crystals than 'phobic' (001) crystals at all three stability conditions.Both the crystals showed different compactibility despite having same particle size, surface area and hardness value.In contrast, milling reduced the predominance of facets [( 100) and ( 001)] on both the crystals and posed similar degradation and compaction behavior.

Inconsistency in drug product quality poses significant challenges in formulation development of BCS class II drugs, since their performance is sensitive to material properties.Within this framework, vast knowledge base has been generated with respect to the impact of polymorphs / pseudopolymorphs / amorphous form on pharmaceutical performance of active pharmaceutical ingredients (APIs).However, the role of crystal habit has remained largely ignored.Anisotropic surface chemistry of different crystal facets in different crystal habits may also affect properties like kinetic solubility, dissolution behavior and in vivo performance.The present investigation deals with crystal habit modification of celecoxib (CLB) and its effect on biopharmaceutical performance.Two crystal habits namely Acicular shape (A-CLB) and Plate shape (P-CLB) of CLB were generated by recrystallization from toluene at 25 °C and 60 °C, respectively.P-CLB exhibited significantly faster dissolution kinetics and intrinsic dissolution rate in pH 12 phosphate buffer compared to A-CLB.The oral bioavailability study showed significantly higher Cmax and shorter Tmax compared to A-CLB.The significant enhancement in biopharmaceutical performance of P-CLB was attributed to its more abundant hydrophilic surfaces than A-CLB.The surface anisotropy of both of the crystal habit was supported by wettability and surface free energy determination from contact angle measurements, surface chemistry determination by X-ray photoelectron spectroscopy (XPS), crystal structure modeling and crystal face indexation.

Febuxostat exhibits unprecedented solid forms with a total of 40 polymorphs and pseudopolymorphs reported. Polymorphs differ in molecular arrangement and conformation, intermolecular interactions, and various physicochemical properties, including mechanical properties. Febuxostat Form Q (FXT Q) and Form H1 (FXT H1) were investigated for crystal structure, nanomechanical parameters, and bulk deformation behavior. FXT Q showed greater compressibility, densification, and plastic deformation as compared to FXT H1 at a given compaction pressure. Lower mechanical hardness of FXT Q (0.214 GPa) as compared to FXT H1 (0.310 GPa) was found to be consistent with greater compressibility and lower mean yield pressure (38 MPa) of FXT Q. Superior compaction behavior of FXT Q was attributed to the presence of active slip systems in crystals which offered greater plastic deformation. By virtue of greater compressibility and densification, FXT Q showed higher tabletability over FXT H1. Significant correlation was found with anticipation that the preferred orientation of molecular planes into a crystal lattice translated nanomechanical parameters to a bulk compaction process. Moreover, prediction of compactibility of materials based on true density or molecular packing should be carefully evaluated, as slip-planes may cause deviation in the structure-property relationship. This study supported how molecular level crystal structure confers a bridge between particle level nanomechanical parameters and bulk level deformation behavior.

Differential surface anisotropy of different crystals of the same API can have a significant impact on their pharmaceutical performance. The present work investigated the impact of differential surface anisotropy of two plate-shaped crystals of aspirin (form I) on their hygroscopicity, stability and compaction behavior. These crystals differed in their predominant facets (100) and (001) and were coded as AE-100 & E-001. (100) facets exposed polar carbonyl groups which provided hydrophilicity to the facets. In contrast, (001) facets possessed hydrophobicity as they exposed non-polar aryl and methyl groups. Both the samples showed different degradation behavior, at various stability conditions (i.e. 40°C/75%RH, 30°C/90%RH and 30°C/60%RH) and different time intervals. Polar groups of aspirin have been reported to be prone to hydrolysis due to which AE-100 was less stable than E-001. Dynamic vapor sorption (DVS) analysis at different simulated stability conditions also supported this observation, wherein AE-100 showed higher moisture sorption than E-001. Both the samples having similar particle size, shape, surface area and hardness value, showed differences in their compactibility. However, milling narrowed down the predominance of facets and both the milled samples showed similar stability and compaction behavior. This study was also supported by surface free energy determination, molecular modeling and face indexation of unmilled and milled samples.

The present work investigates the impact of milling on differential compactibility behavior of celecoxib (CEL) crystal habits. Plate shaped (CEL-P) crystals showed better compactibility over acicular (CEL-A) crystals. Milling improved the compactibility of both the forms. However, despite similar particle shape, size, and surface area, milled fractions of the two habits showed significantly different interparticulate bonding strength. The greater bonding strength of milled CEL-P (MCEL-P) over milled CEL-A (MCEL-A) was attributed to the differential cleavage behavior of the two habits that conferred the different surface molecular environment to the milled powders. The preferred cleavage of CEL-P across {020} plane exposed the -CF3 group and the methyl phenyl ring on the surface of MCEL-P. On the other hand, CEL-A preferentially fractured along their shortest axis that increased the exposure of {100} plane on the surface of MCEL-A, which exposed the -CF3 group and the pyrazole ring. Surface free energy quantified by determining advancing contact angle revealed greater dispersive component of MCEL-P over MCEL-A. This is consistent with the differential cleavage behavior of CEL-P and CEL-A. This confirmed the role of dispersive component of surface free energy in governing interparticulate bonding strength of CEL. The study supports the postulate that tablet tensile strength is governed by the dispersive intermolecular interactions formed over the interparticulate bonding area.

A minor amount of amorphous phase, especially present on the surface of crystalline pharmaceutical actives, can have a significant impact on their processing and performance. Despite the presence of sophisticated analytical tools, detection and quantification of low levels of amorphous content pose significant challenges owing to issues of sensitivity, suitability, limit of detection and limit of quantitation. Current study encompasses the quantification of amorphous content in the crystalline form of celecoxib (CLB) using a dynamic vapor sorption (DVS) based method. Water, used as the solvent probe, achieved equilibration within a very short period of time (i.e. 6 h) due to hydrophobic nature of CLB, thus allowing development of a rapid quantification method. The study included optimization of instrument and sample related parameters for the development of an analytical method. The calibration curve for amorphous CLB in crystalline CLB was prepared in the concentration range of 0–10% w/w. The analytical method was validated for linearity, range, accuracy and precision. The method for quantification was found to be linear with R2 value of 0.999, rapid and sensitive for quantification of low levels of amorphous CLB content. It was able to detect the presence of amorphous phase in a predominantly crystalline phase at concentrations as low as 0.3% w/w. The limit of quantitation was found to be 0.9% w/w. Moreover, the influence of mechanical processing on the amorphous content in crystalline CLB was also investigated.

Crystallization in the presence of Polysorbate-80 (T-80), a non-ionic surfactant was explored for crystal habit modification of nifedipine polymorph I (Nif). A concentration dependent reduction in aspect ratio was observed with T-80. Generation of any new solvates/polymorphs was ruled out by Fourier Transform Infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, and thermogravimetric analysis, while the absence of T-80 on the surface or bulk of the recrystallized samples was established by liquid chromatography mass spectroscopy. The dissolution rate order of the re-crystallized Nif habits was in the order of; Nif-D (Nif with 0.6%v/v T-80)>Nif-C (Nif with 0.4% v/v T-80)>Nif-B (Nif with 0.2% v/v T-80)>Nif-A (plain Nif). Wetting ability and surface free energy determination from contact angle measurements were used to explain the order of dissolution rate. The consequences of varying concentration of T-80 on Nif crystal habit was supported by means of molecular dynamics (MD) which was executed using COMPASS force field while modified attachment energy was computed to acquire the absolute morphology. The mechanism for alteration in the morphology was suggested based on the computed crystal surface chemistry. Nif-D crystal habit was nearly iso-diametric with majority of facets occupied by polar dominant surfaces {011} and {002} which ultimately resulted in higher dissolution rate. In Nif-B and Nif-C the dissolution rate was dependent on the proportion of polar and non-polar facet area. The methodology used in this study could be an influential tool for selection of concentration of habit-modifying additives in other crystallization studies.

Non-polar surface area increased and polar energy decreased resulting in reduction in dissolution rate upon increasing HPMC concentration, from 0% w/v (Nif-0) to 0.6% w/v (Nif-6).

In this work, we studied crystallization kinetics of amorphous hesperetin (HRN) and naringenin (NRN) alone, and in 1:1 proportion with mannitol at Tg + 15 K. Crystallization rate of NRN was found to be significantly higher than HRN. Mannitol accelerated crystallization of HRN as well as NRN. NRN exhibited higher crystallization rate than HRN, in presence of mannitol, as well. Finke-Watzky model was used to deconvolute the crystallization kinetics data into nucleation and crystal growth rate constant. HRN alone had 9.56 × 10(9) times faster nucleation rate and 1.88 times slower crystal growth than NRN alone. Mannitol increased nucleation and crystal growth rate of HRN as well as NRN. In presence of mannitol, HRN possessed 1.34 × 10(10) times faster nucleation rate and 1.70 times slower crystal growth rate than NRN. Differences in crystallization behavior of HRN and NRN were explained by their thermodynamic properties.

Hydroxypropyl methylcellulose (HPMC), a widely employed film coating polymer, exhibits poor dispersibility in an aqueous medium. Rapid hydration leading to swelling and coherent gel formation is reported to be responsible for this problem. Present study focuses on the use of spray drying based approach for co-processing of HPMC to improve its dispersibility. Dispersion behavior of native HPMC showed formation of large lumps that did not dissolve completely for 40 min. However, HPMC co-processed with lactose and sodium chloride exhibited improvement in dispersibility with complete dissolution attained within 20 min. Mechanistic insights into improved dispersibility were obtained using contact angle studies, confocal laser scanning microscopy (CLSM), transmission electron microscopy (TEM) and scanning TEM (STEM) studies. Co-processed products exhibited higher immersional wetting as determined by sessile drop contact angle technique, which indicated spontaneous incursion of water. CLSM study revealed highly swollen and erodible gel in co-processed products. Novel application of TEM and STEM techniques was developed to understand the nature of mixing achieved during co-processing. Overall the improvement in dispersibility of co-processed products was predominantly due to the alteration in sub-particulate level properties during co-processing. The effect of excipients on the film properties of HPMC, like tensile strength and hygroscopicity, was also assessed. This study provides the comprehensive understanding of role of co-processing on improvement of dispersion behavior of HPMC and helps in the selection of suitable excipients for the same.

Cellulose ethers are important materials with numerous applications in pharmaceutical industry. They are widely employed as stabilizers and viscosity enhancers for dispersed systems, binders in granulation process and as film formers for tablets. These polymers, however, exhibit challenge during preparation of their aqueous dispersions. Rapid hydration of their surfaces causes formation of a gel that prevents water from reaching the inner core of the particle. Moreover, the surfaces of these particles become sticky, thus leading to agglomeration, eventually reducing their dispersion kinetics. Numerous procedures have been tested to improve dispersibility of cellulose ethers. These include the use of cross-linking agents, alteration in the synthesis process, adjustment of water content of cellulose ether, modification by attaching hydrophobic substituents and co-processing using various excipients. Among these, co-processing has provided the most encouraging results. This review focuses on the molecular mechanisms responsible for the poor dispersibility of cellulose ethers and the role of co-processing technologies in overcoming the challenge. An attempt has been made to highlight various co-processing techniques and specific role of excipients used for co-processing.

Self emulsifying drug delivery system (SEDDS) has been increasingly used for improving the oral bioavailability of poorly water soluble drugs. SEDDS can be solidified by adsorbing them on different solid carriers. In the present study, the impact of properties of solid carrier on drug release profile from solid SEDDS was investigated. Celecoxib (CEL) loaded supersaturable SEDDS (S-SEDDS) was prepared and optimized by using optimal response surface design. Optimum composition of S-SEDDS corresponded to 10:45:45% v/v ratio of oil (Capryol 90), surfactant (Tween 20) and cosurfactant (Transcutol HP) with Soluplus (40 mg) as precipitation inhibitor. Different grades of silicon dioxide were selected based on their properties like surface area, porosity and hydrophobicity-hydrophilicity, and used for preparation of solid S-SEDDS (SS-SEDDS) by adsorption method. All SS-SEDDS formulations in release studies, gave droplet size, PDI and zeta potential similar to S-SEDDS. The percent drug release after 120min from CEL powder, S-SEDDS and SS-SEDDS with Sylysia 350 fcp, Aerosil 300 Pharma, Aerosil 200 Pharma and Aerosil R 972 Pharma was found to be 0.58%, 100%, 38.44%, 9.63%, 2.53% and 5.99%, respectively. Drug release profiles were compared by using model independent methods. The differential drug release behavior of SS-SEDDS was attributed to the different physico-chemical properties of solid carriers. SS-SEDDS with Sylysia 350 fcp showed higher drug release and greater dissolution efficiency. Oral bioavailability study also demonstrated 2.34 fold increase in Cmax and 4.82 fold increase in AUC (0-24h) when compared with CEL powder. This study highlights the rational for selection of solid carriers in the formulation development of solid SEDDS.

Intrinsic dissolution rate (IDR) is a useful technique to differentiate the solid forms of a drug. In the present study, the impact of crystal habit and crystal size on IDR of celecoxib (CEL) in different media was assessed. The IDR of plate-shaped CEL crystals (CEL-P) (53.4 +/- 6.7 mu g/min/cm(2)) was 46.3% higher than that of acicular crystals (CEL-A) (36.5 +/- 1.7 mu g/min/cm(2)) in pH 12 phosphate buffer. Contact angle experiments and values of dispersive and polar components of surface free energy indicated better wettability of CEL-P compacts than CEL-A. Higher IDR and better wettability of CEL-P were attributed to favorable exposure of hydrophilic crystal facets on compact surface, due to preferred orientation during compaction. In contrast to native samples, milled CEL-A (MCEL-A) and milled CEL-P (MCEL-P) showed similar IDR. Interestingly, IDR of CEL-A (36.5 +/- 1.7 mu g/min/cm(2)) and MCEL-A (35.64 +/- 5.09 mu g/min/cm(2)) did not show any significant difference (p > 0.05). However, IDR of CEL-P (53.4 +/- 6.7 mu g/min/cm(2)) was significantly higher (p < 0.05) than that of MCEL-P (39.15 +/- 2.48 mu g/min/cm(2)). This was ascribed to (i) differential cleavage behavior of CEL-A and CEL-P during milling and (ii) reduced degree of preferred orientation of hydrophilic facets in MCEL-P compacts. This work provides an interesting case study of the impact of particle level properties and surface molecular environment on IDR.

It is well established that pharmaceutical processing can cause disruption of the crystal structure, leading to generation of amorphous content in crystalline materials. The presence of even a small amount of amorphous form, especially on the surface of crystalline material, can affect processing, performance, and stability of a drug product. This necessitates the need to quantify, monitor, and control the amorphous form. Numerous analytical techniques have been reported for the quantification of amorphous phase, but issues of sensitivity, suitability, limit of detection, and quantitation pose significant challenges. The present review focuses on use of dynamic vapor sorption (DVS) for quantification of amorphous content in predominantly crystalline materials. The article discusses (1) theoretical and experimental considerations important for developing a quantification method, (2) methods used for quantification of amorphous content, (3) basis for selecting a suitable methodology depending on the properties of a material, and (4) role of various instrument and sample-related parameters in designing a protocol for quantification of amorphous content. Finally, DVS-based hyphenated techniques have been discussed as they can offer higher sensitivity for quantification of amorphous content.

The present study investigates the potential of spray drying as a technique for generation of pharmaceutical cocrystals. Carbamazepine–Nicotinamide cocrystal (CNC) was chosen as model cocrystal system for this study. Firstly, CNC was generated using liquid assisted grinding and used for generation of phase solubility diagram (PSD) and ternary phase diagram (TPD). Both PSD and TPD were carefully evaluated for phase behavior of CNC when equilibrated with solvent. The undersaturated region with respect to CNC, as depicted by TPD, was selected as target region to initiate cocrystallization experiments. Various points in this region, representative of different compositions of Carbamazepine, Nicotinamide and CNC, were selected and spray drying was carried out. The spray dried product was characterized for solid state properties and was compared with CNC generated by liquid assisted grinding. Spray drying successfully generated CNC of similar quality as those generated by liquid assisted grinding. Moreover, there was no significant impact of process variables on formation of CNC. Spray drying, owing to its simplicity and industrial scalability, can be a promising method for large scale cocrystal generation.

•Crystallization kinetics of amorphous erythromycin salts was assessed.•Contribution of thermodynamic, kinetic and structural factors was evaluated.•Role of counterions on physical stability of amorphous salts was investigated.•Implications of the study: In rationalizing stabilization approach for amorphous form.

Poor biopharmaceutical performance of Bio-pharmaceutical Classification System (BCS) class II drug molecules is a major hurdle in the design and development of pharmaceutical formulations. Anisotropic surface chemistry of different facets in crystalline material affects physicochemical properties, such as wettability, of drugs. In the present investigation, a molecule-centered approach is presented toward crystal habit modification of celecoxib (CEL) and its effect on oral bioavailability. Two crystal habits of CEL, acicular crystal habit (CEL-A) and a plate-shaped crystal habit (CEL-P), were obtained by recrystaffization from toluene at 25 and 60 degrees C, respectively. Compared to CEL-A, CEL-P exhibited significantly faster dissolution kinetics in aqueous media significantly higher C-max and shorter T-max in an oral bioavailability study. The significant enhancement in dissolution and biopharmaceutical performance of CEL-P was attributed to its more abundant hydrophilic surfaces compared to CEL-A. This conclusion was supported by wettability and surface free energy determination from contact angle measurements and surface chemistry determination by X-ray photoelectron spectroscopy (XPS), crystal structure modeling, and crystal face indexation.

The aim of the present study was to investigate differences in surface chemistry of commercially available telmisartan (TMS) samples in Indian market and to correlate them to the surface molecular environment. Comprehensive characterization of material properties of four TMS samples from different sources showed that all samples exhibited same polymorphic form, but different particle shape, particle size distribution, surface energetics and surface chemistry. Wettability and surface free energy were determined using sessile drop contact angle technique. TMS samples exhibited significant variations in their wetting behavior. The role of crystal shape, particle size distribution, surface energetics and surface chemistry in controlling TMS powder wettability was collectively explored by contact angle experiments. Evaluation of work of adhesion (Wa), immersion (Wi) and spreading (Ws) indicated that samples had differential wetting behavior. The surface chemistry was elucidated by X-ray photoelectron spectroscopy (XPS). The surface polarity index was determined by XPS and expressed as (oxygen+nitrogen)-to-(carbon) atomic concentration ratio. It was found to be different for all four TMS samples. Crystal morphology of TMS polymorph A was predicted using Bravais-Friedel Donnay-Harker (BFDH) method. Molecular lipophilic surface potential (MLSP) data for TMS showed the varied surface lipophilic environment throughout the molecule. Hence it can be concluded that the differential abundance of surface elements play an important role in controlling the biopharmaceutical performance of TMS powder samples.

Nanocrystalline solid dispersions (NCSDs) of Indomethacin were prepared by antisolvent precipitation followed by spray drying, using hydrophilic polymers like polyvinyl pyrrolidine (PVP K30), hydroxyl propyl methyl cellulose (HPMC E15) and polyvinyl alocohol (PVA) in the ratio of 90:10 w/w. Methonolic solution of Indomethacin was added to aqueous polymeric solution to obtain nano-crystals of Indomethacin, and was spray dried to obtain NCSDs. Crystallite size of Indomethacin in dispersion was measured using by Scherrer equation, which uses powder X-ray diffraction peak broadening of nano-crystallites over micro-crystallites. The average crystallite size of Indomethacin in dispersions was lowest in PVA dispersion followed by HPMC E15 and PVP K30. NCSDs showed considerably higher dissolution rate over crystalline solid dispersions and "as received" Indomethacin in water. NCSDs released 80 - 90% of Indomethacin within 10 min in comparison to 25-50% in case of crystalline solid dispersion and < 5% incase of "as received" Indomethacin. Higher dissolution efficiency of nanocrystalline solid dispersions could be attributed to the nano-size of Indomethacin crystallites, and crystal growth inhibition role of polymers. Influence of viscosity and drug-excipient miscibility (solubility parameter), of polymers used in the present study, on the crystallite size is discussed.