Crystal morphology engineering of pharmaceutical solids: tabletting performance enhancement.

Crystal morphology engineering of a macrolide antibiotic, erythromycin A dihydrate, was investigated as a tool for tailoring tabletting performance of pharmaceutical solids. Crystal habit modification was induced by using a common pharmaceutical excipient, hydroxypropyl cellulose, as an additive during crystallization from solution. Observed morphology of the crystals was compared with the predicted Bravais-Friedel-Donnay-Harker morphology. An analysis of the molecular arrangements along the three dominant crystal faces [(002), (011), and (101)] was carried out using molecular simulation and thus the nature of the host-additive interactions was deduced. The crystals with modified habit showed improved compaction properties as compared with those of unmodified crystals. Overall, the results of this study proved that crystal morphology engineering is a valuable tool for enhancing tabletting properties of active pharmaceutical ingredients and thus of utmost practical value.

A new insight into solid-state conformation of macrolide antibiotics.

Quantitative analysis of the molecular conformations of the 14-membered macrolide antibiotics erythromycin A and B, clarithromycin, and roxithromycin in the solid state was performed. While the erythronolide macrocycle adopts a very similar folded-out conformation in all the macrolides studied, the proximity of the monosaccharide moieties, L-cladinose and D-desosamine, to each other is demonstrated to be the distinctive feature of their molecular conformations, based on atom-atom interaction energy analysis. More surprisingly, the common features in the relative orientation of the monosaccharide moieties (in terms of non-bonded atom-atom interactions) were revealed between the 14- and 15-membered (azithromycin) macrolide antibiotics. Herein we report on the details of the spatial arrangement of the monosaccharide moieties in these structurally related drug molecules and their influence on the biopharmaceutical properties of erythromycin derivatives.

Phase transformations of erythromycin A dihydrate during pelletisation and drying.

An at-line process analytical approach was applied to better understand process-induced transformations of erythromycin dihydrate during pellet manufacture (extrusion-spheronisation and drying process). The pellets contained 50% (w/w) erythromycin dihydrate and 50% (w/w) microcrystalline cellulose, with purified water used as a granulating fluid. To characterise changes in solid-state properties during processing, near infrared (NIR) spectroscopy and X-ray powder diffraction (XRPD) were applied. Samples were taken after every processing step (blending, granulation, extrusion, and spheronisation) and at predetermined intervals during drying at 30 or 60 degrees C. During pelletisation and drying at 30 degrees C no changes occurred. Partial transformation to the dehydrated form was observed for the pellets dried at 60 degrees C by NIR and XRPD. The variable temperature XRPD measurements of the wet pellets (from 25 to 200 degrees C) also confirmed the change to erythromycin dehydrate at approximately 60 degrees C.

Solid-state properties and relationship between anhydrate and monohydrate of baclofen.

Baclofen, a widely used antispastic agent, has been found to exist in two crystalline forms, the anhydrate and monohydrate. The aim of this study was (1) to identify and characterize these two solid phases of baclofen, and (2) to examine the processing-induced phase transformations associated with wet granulation of baclofen. Using multiple techniques (powder X-ray diffraction, thermal analysis, vibrational spectroscopy and water vapor sorption analysis), a structural relationship has been established between the anhydrate and monohydrate of baclofen. Thermal and variable-temperature powder X-ray diffraction data indicate that the monohydrate, which presumably belongs to the channel hydrate class, dehydrates at 60 degrees C with the formation of the anhydrate. Furthermore, the anhydrate to monohydrate transformation followed by optical microscopy was found to occur via a solvent-mediated route. During wet massing experiments, the critical moisture value for the hydrate formation under the conditions of the present study was identified using qualitative powder X-ray diffraction and Raman spectroscopy. Finally, the interconversion pathway between the two crystalline forms of baclofen was presented. The knowledge of this pathway provides better understanding and control of the solid state of baclofen during processing and storage.

Multivariate data analysis as a fast tool in evaluation of solid state phenomena.

A thorough understanding of solid state properties is of growing importance. It is often necessary to apply multiple techniques offering complementary information to fully understand the solid state behavior of a given compound and the relations between various polymorphic forms. The vast amount of information generated can be overwhelming and the need for more effective data analysis tools is well recognized. The aim of this study was to investigate the use of multivariate data analysis, in particular principal component analysis (PCA), for fast analysis of solid state information. The data sets analyzed covered dehydration phenomena of a set of hydrates followed by variable temperature X-ray powder diffractometry and Raman spectroscopy and the crystallization of amorphous lactose monitored by Raman spectroscopy. Identification of different transitional states upon the dehydration enabled the molecular level interpretation of the structural changes related to the loss of water, as well as interpretation of the phenomena related to the crystallization. The critical temperatures or critical time points were identified easily using the principal component analysis. The variables (diffraction angles or wavenumbers) that changed could be identified by the careful interpretation of the loadings plots. The PCA approach provides an effective tool for fast screening of solid state information.

Understanding processing-induced phase transformations in erythromycin-PEG 6000 solid dispersions.

Since the quality and performance of a pharmaceutical solid formulation depend on solid state of the drug and excipients, a thorough investigation of potential processing-induced transformations (PITs) of the ingredients is required. In this study, the physical phenomena taking place during formulation of erythromycin (EM) dihydrate solid dispersions with polyethylene glycol (PEG) 6000 by melting were investigated. PITs were monitored in situ using variable temperature X-ray powder diffraction (VT-XRPD), differential scanning calorimetry (DSC), and hot-stage microscopy (HSM). Possible intermolecular interactions between the drug and polymer in the solid state were further studied by Fourier transform infrared (FTIR) spectroscopy. While in the absence of PEG the dehydration was the only transformation observed, hot-melt processing with the polymer caused the drug to undergo multiple phase transformations (EM dihydrate --> EM dehydrate --> EM anhydrate). This alteration in phase behavior of EM was attributed to the ability of PEG in promoting nucleation and crystal growth of the EM anhydrate through a solvent-mediated route. In situ monitoring of solid dispersion formation, especially by VT-XRPD and HSM, enabled both early-stage detection of phase transformations during the hot-melt processing and better process understanding.

Influence of solvents on the variety of crystalline forms of erythromycin.

The influence of the organic solvents widely used in the pharmaceutical industry (acetone, methylethylketone, ethanol, and isopropanol) both in the presence and in the absence of water on the crystallization behavior of erythromycin (Em), a clinically relevant antibiotic of the macrolide group, was investigated. It was observed that despite a high preference for water as a guest molecule, Em rather easily forms solvates with the organic solvents studied. Consequently, 4 distinct solvates of Em have been isolated by recrystallization: acetonate, methylethylketonate, ethanolate, and isopropanolate. It was established that in a pure organic solvent, or 1:9 or 1:1 water-organic solvent mixtures, the corresponding solvate is always crystallized. However, the recrystallization of erythromycin from 2:1 water-organic solvent (excluding methylethylketone) mixture results in the formation of a crystal hydrate form. X-ray powder diffraction revealed the isostructurality of the solvates with acetone and methylethylketone. Thermogravimetric analysis showed that the loss of volatiles by all of the solvated crystals is nonstoichiometric. The desolvation behavior of the solvates with the organic solvents studied by means of variable-temperature x-ray powder diffraction indicates that in contrast to erythromycin dihydrate, they belong to a different class of solvates--those that produce an amorphous material upon desolvation.

Microfluidics-assisted engineering of polymeric microcapsules with high encapsulation efficiency for protein drug delivery.

In this study, microfluidic technology was employed to develop protein formulations. The microcapsules were produced with a biphasic flow to create water-oil-water (W/O/W) double emulsion droplets with ultrathin shells. Optimized microcapsule formulations containing 1% (w/w) bovine serum albumin (BSA) in the inner phase were prepared with poly(vinyl alcohol), polycaprolactone and polyethylene glycol. All the particles were found to be intact and with a particle size of 23-47 µm. Furthermore, the particles were monodisperse, non-porous and stable up to 4 weeks. The encapsulation efficiency of BSA in the microcapsules was 84%. The microcapsules released 30% of their content within 168 h. This study demonstrates that microfluidics is a powerful technique for engineering formulations for therapeutic proteins.

A new cocrystal and salts of itraconazole: comparison of solid-state properties, stability and dissolution behavior.

Cocrystallization and salt formation have been shown to entail substantial promise in tailoring the physicochemical properties of drug compounds, in particular, their dissolution and hygroscopicity. In this work, we report on the preparation and comparative evaluation of a new cocrystal of itraconazole and malonic acid and two new hydrochloric salts (dihydrochloride and trihydrochloride) of itraconazole. The intrinsic dissolution rate, hygroscopicity, and thermodynamic stability were determined for the obtained solid-state forms and compared to itraconazole-succinic acid (2:1) cocrystal. The results show that the solid-state forms with higher intrinsic dissolution rate are less stable. Both itraconazole salts exhibited the highest dissolution rate, but also demonstrated high hygroscopicity at relative humidity above 70%. The new cocrystal, in contrast, were found to increase the dissolution rate of the parent drug by about 5-fold without compromising the hygroscopicity and the stability. This study demonstrates that, for dissolution rate enhancement of poorly water-soluble weak bases, cocrystallization is a more suitable approach than hydrochloric salt formation.

Enhanced Dissolution and Oral Bioavailability of Piroxicam Formulations: Modulating Effect of Phospholipids.

Several biologically relevant phospholipids were assessed as potential carriers/additives for rapidly dissolving solid formulations of piroxicam (Biopharmaceutics Classification System Class II drug). On the basis of in vitro dissolution studies, dimyristoylphosphatidylglycerol (DMPG) was ranked as the first potent dissolution rate enhancer for the model drug. Subsequently, the solid dispersions of varying piroxicam/DMPG ratios were prepared and further investigated. Within the concentration range studied (6.4-16.7 wt %), the dissolution rate of piroxicam from the solid dispersions appeared to increase as a function of the carrier weight fraction, whereas the cumulative drug concentration was not significantly affected by piroxicam/DMPG ratio, presumably due to a unique phase behavior of the aqueous dispersions of this carrier phospholipid. Solid state analysis of DMPG-based formulations reveled that they are two-component systems, with a less thermodynamically stable form of piroxicam (Form II) being dispersed within the carrier. Finally, oral bioavailability of piroxicam from the DMPG-based formulations in rats was found to be superior to that of the control, as indicated by the bioavailability parameters, cmax and especially Tmax (53 µg/mL within 2 h vs. 39 µg/mL within 5.5 h, respectively). Hence, DMPG was regarded as the most promising carrier phospholipid for enhancing oral bioavailability of piroxicam and potentially other Class II drugs.

Pharmaceutical co-crystals-an opportunity for drug product enhancement.

By maximizing our understanding of materials and the relative importance of interactions on all levels (i.e., molecular, particle, powder, product), we can improve the manufacture of drug dosage forms and thus meet target specifications for mechanical durability, stability and biopharmaceutical performance. Pharmaceutical co-crystals are the latest material being explored in order to enhance drug properties using this bottom-up approach. In this review we provide a general introduction to pharmaceutical co-crystals. We also address common aspects of co-crystal formation, discuss screening strategies and outline methodologies for co-crystal functionality. Pharmaceutical co-crystals that have a distinct solid phase possess a unique set of properties, thus co-crystal formation can act as an advantageous alternative to other solid-state modification techniques. More research is needed in order to scale up co-crystal systems and implement manufacturing of final dosage forms on large scale.

Nanodispersions of taxifolin: impact of solid-state properties on dissolution behavior.

Nanosizing is an advanced formulation approach to address the issues of poor aqueous solubility of active pharmaceutical ingredients. Here we present a procedure to prepare a nanoparticulate formulation with the objective to enhance dissolution kinetics of taxifolin dihydrate, a naturally occurring flavonoid with antioxidant, anti-inflammatory, and hepatoprotective activities. Polyvinylpirrolidone was selected as a carrier and the solid nanodispersions of varying compositions were prepared by a co-precipitation technique followed by lyophilization. The formulation technology reported herein resulted in aggregate-free, spherical particles with the mean size of about 150 nm, as observed by scanning electron microscopy and measured by photon correlation spectroscopy. Furthermore, the co-precipitation process caused taxifolin dihydrate to convert into an amorphous form as verified by X-ray powder diffraction, differential scanning calorimetry, hot stage microscopy and Raman spectroscopy. Finally, in vitro dissolution behavior of the nanodispersion of taxifolin was shown to be superior to that of either pure drug or a drug-polymer physical mixture, reaching 90% of taxifolin released after 30 min. Such enhanced drug release kinetics from the nanodispersion was attributed to both the reduced particle size and the loss of crystallinity.

Phase transformation of erythromycin A dihydrate during fluid bed drying.

An in-line near infrared (NIR) spectrometer was employed to monitor phase transformations of erythromycin dihydrate during a miniaturized fluid bed drying process. The pellets, containing 50% (w/w) erythromycin dihydrate and 50% (w/w) microcrystalline cellulose, were dried at 30, 45, and 60 degrees C. Principal component analysis was used to determine solid-state changes. For this purpose the wavelength range of 1360-2000 nm was selected and preprocessed to remove multiplicative effects. Transformation to erythromycin dehydrate was observed for the pellets dried at 45 and 60 degrees C by NIR spectrometry and X-ray powder diffractometry (XRPD). The formation of erythromycin dehydrate was observed at a moisture content 1.4% (w/w) (mass of water per dry mass of sample) while at 1.8% (w/w) neither XRPD nor NIR were able to detect dehydration. Transformation to erythromycin dehydrate therefore depends strongly on the moisture content of the pellets.