Evaluation of Different Mathematical Methods Describing Drug Liberation from New, “Soft-Patch” Type Matrix Systems

The thermodynamically most stable polymorph under ambient conditions is almost without exception the most desirable crystalline form for development by a pharmaceutical company. It is, therefore, beneficial to discover and to characterize this polymorph at the earliest possible stage of development. A screen for discovering the stable polymorph of a pharmaceutical compound early in the drug discovery–development process is developed and described. In this screen, a small amount of compound is suspended in a diverse group of solvents for two weeks in an effort to crystallize the most stable polymorph. The solubility of the compound in each solvent utilized in the stable polymorph screen is also simultaneously determined using a simple gravimetric method. Ritonavir and an early development candidate (Pfizer compound A) are used as model compounds to demonstrate the utility of the screen for finding the stable polymorph early in the drug discovery–development process.     

Identifying the stable polymorph early in the drug discovery-development process

The thermodynamically most stable polymorph under ambient conditions is almost without exception the most desirable crystalline form for development by a pharmaceutical company. It is, therefore, beneficial to discover and to characterize this polymorph at the earliest possible stage of development. A screen for discovering the stable polymorph of a pharmaceutical compound early in the drug discovery-development process is developed and described. In this screen, a small amount of compound is suspended in a diverse group of solvents for two weeks in an effort to crystallize the most stable polymorph. The solubility of the compound in each solvent utilized in the stable polymorph screen is also simultaneously determined using a simple gravimetric method. Ritonavir and an early development candidate (Pfizer compound A) are used as model compounds to demonstrate the utility of the screen for finding the stable polymorph early in the drug discovery-development process.     

聚合物异相成核对加巴喷丁晶型的控制和选择

药物晶型对药物的物理、化学和生物利用度等诸多性能具有重要的影响。本文通过聚合物异相成核研究了加巴喷丁晶型的培养方法, 以X-射线粉末衍射、红外光谱、DSC分析等方法对培养的加巴喷丁晶型进行了分析和表征。结果表明, 聚合物异相成核是一种对加巴喷丁进行晶型选择和控制的有效方法, 本文不但培养了加巴喷丁所有已知的晶型, 而且还发现了一种新的加巴喷丁晶型。     

Determination of polymorph conversion of an active pharmaceutical ingredient in wet granulation using NIR calibration models generated from the premix blends

Near infrared (NIR) spectroscopy was used for quantitatively monitoring polymorph conversion of an active pharmaceutical ingredient (API) in wet granulation. The API under pharmaceutical development has two different polymorphs. Polymorph A is the stable form for drug development and polymorph B is the undesired form produced at elevated temperature and humidity. Because a reference method was not available for quantitation of polymorph B, a calibration set was not readily available for NIR method development. Analysis of NIR spectra of different polymorphs of the API, the premix blend and wet granulation samples revealed narrow spectral regions, which were unique to polymorph B and insensitive to differences in physical properties between the premix blend and wet granulation. Therefore, the premix blend samples spiked with polymorph B were used as the calibration set. The final univariate NIR method can be used for off-line or on-line monitoring of polymorph conversion in the wet granulation process.     

Characterization and superficial transformations on mini-matrices made of interpolymer complexes of chitosan and carboxymethylcellulose during in vitro clarithromycin release

Different interpolymer complexes (IPCs) of chitosan (CS) and carboxymethylcellulose sodium salt (CMC) were used to elaborate mini-matrices containing clarithromycin (CAM). IPCs were characterized by FTIR, DSC and powder X-ray (XRD).Compression processes did not modify the physical state of CAM which was in its polymorph Form II. However, during tableting, polymer/polymer interactions occurred to form matrix systems that were confirmed by DSC.When mini-matrices were placed in acetate buffer (pH 4.2), the formation of a CAM solvate was determined by XRD, FTIR and DSC, showing the presence of incorporated crystallizing solvent molecules. Grazing incidence X-ray diffraction (GID) enabled us to profile transformations of CAM on surfaces of mini-matrices when it is in intimate contact with dissolution medium, and its conversion to a solvate form prior to its dissolution process. Besides, FTIR and DSC revealed polymer–polymer electrostatic interactions during dissolution process.Furthermore, swelling and eroding studies and in vitro drug release exhibited that when increasing the amount of CS within IPCs, swelling and erosion rates were greater and CAM release was faster. Zero-order kinetics from drug release profiles were related to linear erosion kinetics, and highlighted that erosion played an important role in drug release due to CAM poor solubility at this pH.     

Crystalline solids

Many drugs exist in the crystalline solid state due to reasons of stability and ease of handling during the various stages of drug development. Crystalline solids can exist in the form of polymorphs, solvates or hydrates. Phase transitions such as polymorph interconversion, desolvation of solvate, formation of hydrate and conversion of crystalline to amorphous form may occur during various pharmaceutical processes, which may alter the dissolution rate and transport characteristics of the drug. Hence it is desirable to choose the most suitable and stable form of the drug in the initial stages of drug development. The current focus of research in the solid-state area is to understand the origins of polymorphism at the molecular level, and to predict and prepare the most stable polymorph of a drug. The recent advances in computational tools allow the prediction of possible polymorphs of the drug from its molecular structure. Sensitive analytical methods are being developed to understand the nature of polymorphism and to characterize the various crystalline forms of a drug in its dosage form. The aim of this review is to emphasize the recent advances made in the area of prediction and characterization of polymorphs and solvates, to address the current challenges faced by pharmaceutical scientists and to anticipate future developments.     

Pressure-temperature state diagram for the phase relationships between benfluorex hydrochloride forms I and II: a case of enantiotropic behavior

The active pharmaceutical ingredient racemic benfluorex hydrochloride (benfluorex-HCl) has an interesting phase behavior due to an elusive solid-solid phase transition. The stability hierarchy between different phases is often determined based on heat-related experiments only or slurry interconversion. It is shown that if pressure and volume are taken into account, not only the phase equilibria are correctly positioned in the pressure-temperature phase diagram, but the experimental data also improves. Thus, it has been found that the racemic benfluorex-HCl is enantiotropic under "ordinary conditions" with polymorph II and polymorph I, respectively, being the low- and the high-temperature phases. Above ～ 151 MPa, the system becomes monotropic and polymorph II is the single stable phase.     

Investigation of the phase transitions occurring during and after the dehydration of xylazine hydrochloride monohydrate

This paper reports an investigation of a complex solid state phase transition where two inter-converting polymorphs (X and A) of the pharmaceutical molecule xylazine hydrochloride formed and transformed during and after the dehydration of its monohydrate (H). The crystal structures of all three forms were compared. During the investigation of this solid state phase transition it was determined that the dehydration of H produced either a pure X form, or a mixture of the X and A forms. The phase composition depended on the sample preparation procedure and the experimental conditions. It was found that grinding of the hydrate enhanced the formation of polymorph X as a product of dehydration, whereas higher humidity, temperature, or mechanical compression enhanced the formation of polymorph A. The transition mechanism of this complex process was analysed and explained by taking into account the crystal structures of these three forms.     

Novel polymorphic form of adefovir dipivoxil derived from polymer-directed crystallization

Crystallization is an essential step in pharmaceutical processing. The discovery of a non-classical crystallization pathway would be a promising strategy to engineer the properties of drug crystalline particles for specific delivery conditions. Herein, polymer-directed crystallization was successfully employed to modify the characteristics of a model drug, adefovir dipivoxil (AD). Polyacrylic acid (PAA), ethyl cellulose (EC), and hydroxypropyl cellulose were added as active polymers to control the crystallization pathway of AD. Changes in crystal habit were observed in all cases. A novel polymorph was found after the addition of PAA and EC, and was confirmed by XRD and DSC results. In FTIR investigations, the crystals derived from PAA-directed crystallization showed strong interactions between PAA and AD. The polymer content in polymer-directed crystallization-derived powders varied from 7 to 24 wt%, and the presence of polymers lead to sustained release of AD. These results make polymer-directed crystallization a simple and efficient technique to engineer the physical and chemical properties of drug crystals.     

Interfacial properties of polymethyl alpha-cyanoacrylate and polybutyl alpha-cyanoacrylate.

Several physical properties of two polyalkyl alpha-cyanoacrylates relevant to their use in pharmaceutical dosage forms have been investigated. Formation of polymer films at several oil-water interfaces reveals films of diverse morphology. The retardation of solute transfer across an oil-water interface caused by the presence of polymer films formed in situ from the monomers has revealed that the methyl derivative forms the more effective barrier to the test solute, gentian violet. The emulsion-stabilizing properties of the methyl polymer have been studied, and the film-forming properties of the monomers spread from benzene onto water surfaces have been examined using a surface balance.     

The effect of pH on polymorph formation of the pharmaceutically active compound tianeptine

The anti-depressant pharmaceutical tianeptine has been investigated to determine the dynamics of polymorph formation under various pH conditions. By varying the pH two crystalline polymorphs were isolated. The molecular and crystal structures have been determined to identify the two polymorphs. One polymorph is an amino carboxylic acid and the other polymorph is a zwitterion. In the solid state the tianeptine moieties are bonded through hydrogen bonds. The zwitterion was found to be less stable and transformed to the acid form. During this investigation an amorphous form was identified.     

Effect of plasma-treatment on suppression of drug adsorption to the surface of plastic infusion bag

Plastics has been widely used at the hospitals and dominates the field of the manufacture of infusion bag sets and packaging materials as a disposable product. Recently, it has been reported, however, that expected drug effects could not be obtained owing mainly to the drug adsorption to the surface of plastic bags observed when several injection drugs such as nitroglycerin, isosorbide dinitrate, diazepam, and insulin were injected mixedly into a certain plastic intravenous bags. And there is a possibility of the occurrence of chemical reactions between the added drugs and the surface of plastic bags. We also can not deny the possibility of the dissolution of softener from the plastic bags. On the other hand, we have been working on the nature of plasma treatment of polymer surfaces by irradiation of low temperature plasma and its pharmaceutical application studies. In this study, we obtained the data concerning the effect of plasma treatment on the reduction of adsorption of insulin to the surface of ethylene-vinylacetate (EVA) bag.     

The computational prediction of pharmaceutical crystal structures and polymorphism

A computational method of predicting all the polymorphs of an organic molecule would be a valuable complement to polymorph screening in the developmental phase. Such a computational method is in its early stages of development, and the current methodologies, which are based on searches for the most stable lattice structure, are critically reviewed. This crude thermodynamic approach generally overestimates the propensity for polymorphism, at least for most of the molecules studied so far, showing the need to model kinetic effects as well as to refine the thermodynamic models. Although the ultimate goal of these studies is still far off, computational predictions of crystal structures have proved useful in aiding the characterisation of polymorphs from powder X-ray data, and in providing insights into the range of types of packing that may be adopted by a given molecule. Thus, computational studies already have the potential to be a valuable tool in pharmaceutical solid state science.     

Insight to the Thermodynamic Stability of Molecular Crystals through Crystallographic Studies of a Multipolymorph System

Five solvent-free polymorphs of a pharmaceutical compound were discovered during polymorph screening. Out of the five polymorphs, only one has strong intermolecular N–H···N hydrogen bonding, whereas the others exhibit only weak C–H···N and π–π stacking interactions in addition to all the other weak C–H···X and van der Waals interactions. The relative thermodynamic stability relationships among the polymorphs are not intuitive and quite complex due to enantiotropic phase behavior. For instance, the polymorph with the most efficient packing (i.e., highest density) is not always the most thermodynamically stable form, and the polymorph with strong intermolecular interactions is not thermodynamically more stable than the polymorph with weak intermolecular interactions at all temperatures. Nevertheless, systematic examination and comparison of the molecular packing and intermolecular interactions of these polymorphs provide insight into the importance of H-bonding and packing efficiency to the thermodynamic stability of a crystalline form, and how these effects are dependent on temperature. This study seeks to correlate single-crystal structure features with experimentally established thermodynamic stability, and provides an example where a polymorph with only van der Waals forces and weak intermolecular interactions can be more stable than a polymorph that displays strong H-bonding in its structural make-up. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3423–3431, 2014     

The Relationship Between the Glass Transition Temperature and the Water Content of Amorphous Pharmaceutical Solids

The glass transition temperature of an amorphous pharmaceutical solid is a critical physical property which can dramatically influence its chemical stability, physical stability, and viscoelastic properties. Water frequently acts as a potent plasticizer for such materials, and since many amorphous solids spontaneously absorb water from their surroundings the relationship between the glass transition temperature and the water content of these materials is important. For a wide range of amorphous and partially amorphous pharmaceutical solids, it was found that there is a rapid initial reduction in the glass transition temperature from the dry state as water is absorbed, followed by a gradual leveling off of the response at higher water contents. This plasticization effect could generally be described using a simplified form of the Gordon–Taylor/ Kelley–Bueche relationships derived from polymer free volume theory. Most of the systems considered showed a nearly ideal volume additivity and negligible tendency to interact. This is consistent with the hypothesis that such mixtures behave as concentrated polymer solutions and indicates that water acts as a plasticizer in a way similar to that of other small molecules and not through any specific or stoichiometric interaction process(es).     

Solubility of Small-Molecule Crystals in Polymers: <Emphasis Type="SmallCaps">d</Emphasis>-Mannitol in PVP,Indomethacin in PVP/VA,and Nifedipine in PVP/VA

Objective  Amorphous pharmaceuticals, a viable approach to enhancing bioavailability, must be stable against crystallization. An amorphous drug can be stabilized by dispersing it in a polymer matrix. To implement this approach, it is desirable to know the drug’s solubility in the chosen polymer, which defines the maximal drug loading without risk of crystallization. Measuring the solubility of a crystalline drug in a polymer is difficult because the high viscosity of polymers makes achieving solubility equilibrium difficult. Method  Differential Scanning Calorimetry (DSC) was used to detect dissolution endpoints of solute/polymer mixtures prepared by cryomilling. This method was validated against other solubility-indicating methods. Results  The solubilities of several small-molecule crystals in polymers were measured for the first time near the glass transition temperature, including d-mannitol (β polymorph) in PVP, indomethacin (γ polymorph) in PVP/VA, and nifedipine (α polymorph) in PVP/VA. Conclusion  A DSC method was developed for measuring the solubility of crystalline drugs in polymers. Cryomilling the components prior to DSC analysis improved the uniformity of the mixtures and facilitated the determination of dissolution endpoints. This method has the potential of providing useful data for designing physically stable formulations of amorphous drugs.     

Far-Infrared Spectroscopy as a Probe for Polymorph Discrimination

Pharmaceutical crystalline polymorph and amorphous form detection and quantification is a standard requirement in the pharmaceutical industry. Infrared (IR) spectroscopy provides an important probe for the characterization of polymorphs. Nonetheless, characterization and discrimination among polymorphs using mid-IR spectroscopy is not always possible in part because the technique mainly probes vibrational modes arising from functional groups in the sample. In the present work, far-IR spectroscopy is demonstrated for the discrimination of polymorphs. This region is influenced by delocalized lattice vibrational modes derived from intermolecular forces and packing arrangements in the crystal structure. A total of 10 polymorphic pharmaceuticals were prepared to conduct a critical evaluation of the question, does this far-IR region add value for polymorph differentiation? It is demonstrated that the far-IR region offers high discriminating power for polymorphs compared to the mid-IR spectral region. In addition, structural similarity and dissimilarity in polymorphic packing arrangements can be derived from this analysis.     

The use of polymer-based electrospun nanofibers containing amorphous drug dispersions for the delivery of poorly water-soluble pharmaceuticals

Electrostatic spinning was applied to the preparation of drug-laden nanofiber for potential use in oral and topical drug delivery. While this technique is in its infancy with regard to pharmaceutical applications, a number of recent publications suggest that it may be of high value in the formulation of poorly water-soluble drugs by combining nanotechnology and solid solution/dispersion methodologies. The purpose of this article is to describe some of these recently published applications. For immediate release oral application, a water-soluble cellulose polymer was selected (i.e., hydroxypropylmethylcellulose, HPMC) while for topical application, a nonbiodegradable, water-insoluble polymer was investigated (i.e., a segmented polyurethane, SPU). Solutions of the polymer and the drugs in appropriate solvents could be spun across various potentials (16-24 kV) generating nanofibers with diameters ranging from 300 to 2000 nm. Dissolution studies found that the non-woven fabrics derived from HPMC and containing itraconazole dissolved over a time course of minutes to hours depending on the formulation used as well as the drug/polymer ratios. Drug release from the SPU samples was dependent on the incorporated drug as well as nanostructure obtained.     

Influence of polyethylene glycol 4000 on the polymorphic forms of diflunisal.

The present study was carried out to investigate the physico-chemical characteristics of diflunisal-PEG 4000 solid dispersions prepared by melting, solvent and melting-solvent methods. The solvents chosen were chloroform, methanol and ethanol-water due to the fact that the drug presents different polymorphic forms in these solvents. The characterization of solid dispersions was performed by X-ray powder diffraction because this technique has the advantage over other identification methods that it can detect both drug and ligand simultaneously. The X-ray diffraction patterns of the diflunisal-PEG systems suggested that the drug/polymer ratio and the solvent nature play an important role in the crystallization of the drug. In this regard, diflunisal crystallizes in form I at high concentrations of the drug (drug/polymer 2:1) in the solidified melt dispersions, however, polymorph III is mainly obtained as the polymer content increases (1:1 and 2:3). Likewise, in solid systems obtained by the solvent and melting solvent methods the drug solidifies in form III in ethanol/water and methanol while polymorph IV crystallizes in chloroform. Finally, DSC thermograms and hot-stage microscopy data of solid dispersions prepared by the melting method have allowed to draw the diflunisal-PEG 4000 solid-liquid phase diagram.