Analysis of solid‐state transformations of pharmaceutical compounds using vibrational spectroscopy

Objectives Solid‐state transformations may occur during any stage of pharmaceutical processing and upon storage of a solid dosage form. Early detection and quantification of these transformations during the manufacture of solid dosage forms is important since the physical form of an active pharmaceutical ingredient can significantly influence its processing behaviour, including powder flow and compressibility, and biopharmaceutical properties such as solubility, dissolution rate and bioavailability. Key findings Vibrational spectroscopic techniques such as infrared, near‐infrared, Raman and, most recently, terahertz pulsed spectroscopy have become popular for solidstate analysis since they are fast and non‐destructive and allow solid‐state changes to be probed at the molecular level. In particular, Raman and near‐infrared spectroscopy, which require no sample preparation, are now commonly used coupled to fibreoptic probes and are able to characterise solid‐state conversions in‐line. Traditionally, uni‐ or bivariate approaches have been used to analyse spectroscopic data sets; however, recently the simultaneous detection of several solid‐state forms has been increasingly performed using multivariate approaches where even overlapping spectral bands can be analysed. Summary This review discusses the applications of different vibrational spectroscopic techniques to detect and monitor solid‐state transformations possible for crystalline polymorphs, hydrates and amorphous forms of pharmaceutical compounds. In this context, the theoretical basis of solid‐state transformations and vibrational spectroscopy and common experimental approaches are described, including recent methods of data analysis.     

Influence of particle size and preparation methods on the physical and chemical stability of amorphous simvastatin

This study investigated the factors influencing the stability of amorphous simvastatin. Quench-cooled amorphous simvastatin in two particle size ranges, 150-180 μm (QC-big) and ?10 μm (QC-small), and cryo-milled amorphous simvastatin (CM) were prepared, and their physical and chemical stability were investigated. Physical stability (crystallization) of amorphous simvastatin stored at two conditions was monitored by X-ray powder diffractometry (XRPD) and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS). Assessment of enthalpy relaxation of amorphous forms was conducted using DSC in order to link the physical and chemical stability with molecular mobility. Chemical stability was studied with high-performance liquid chromatography (HPLC). Results obtained from the current study revealed that the solubility of amorphous forms prepared by both methods was enhanced compared to the crystalline form. The rank of solubility was found to be QC-big = QC-small > CM > crystalline. For the physical stability, the highest crystallization rate was observed for CM, and the slowest rate was detected for QC-big, with an intermediate rate occurring for QC-small. QC exhibited lower molecular mobility and higher chemical degradation than CM. Therefore, the current study demonstrated that QC and CM have obvious differences in both physical and chemical properties. It was concluded that care should be taken when choosing preparation methods for making amorphous materials. Furthermore, particle size, a factor that has often been overlooked when dealing with amorphous materials, was shown to have an influence on physical stability of amorphous simvastatin.     

Disordered drug delivery: destiny,dynamics and the Deborah number

"Disordered drug delivery" is an innovative approach to improving the performance of new chemical entities delivered to the human body. In this technique, the molecules of the drug and/or its delivery system are kinetically trapped in a high energy non-crystalline state. The resulting disordered or "amorphous" material offers potential increases in solubility and biological activity of many thousand fold compared with more conventional crystalline forms of the drug. Despite having a molecular level structure akin to that of liquids, amorphous materials have macroscopic properties that are typical of solids and thus they may be presented to the patient in the form of a convenient solid dosage form. Significant advances in the fundamental understanding of amorphous pharmaceutical materials in the past ten years have permitted major steps forward in the rational design of disordered drug delivery systems. Recognition of significant levels of molecular mobility in the glassy regime and an in-depth appreciation of molecular relaxation times and their distributions have enabled rapid progress to be made in this field. Needs for the future include analytical techniques that can elucidate the complex, dynamic and heterogeneous structure of amorphous materials and reliable models to predict the physical stability and in-vivo performance of disordered drug delivery systems. There are also significant opportunities for the production of disordered drug delivery systems with tailor-made properties through the careful engineering of custom amorphous alloys.     

Physical Stability of Amorphous Solid Dispersions: a Physicochemical Perspective with Thermodynamic,Kinetic and Environmental Aspects

Purpose

Amorphous solid dispersions (ASDs) have been widely used in the pharmaceutical industry for solubility enhancementof poorly water-soluble drugs. The physical stability, however, remainsone of the most challenging issues for the formulation development.Many factors can affect the physical stability via different mechanisms, and therefore an in-depth understanding on these factors isrequired.

Methods

In this review, we intend to summarize the physical stability of ASDsfrom a physicochemical perspective whereby factors that can influence the physical stability areclassified into thermodynamic, kinetic and environmental aspects.

Results

The drug-polymer miscibility and solubility are consideredas the main thermodynamicfactors which may determine the spontaneity of the occurrence of the physical instabilityof ASDs. Glass-transition temperature,molecular mobility, manufacturing process,physical stabilityof amorphous drugs, and drug-polymerinteractionsareconsideredas the kinetic factors which areassociated with the kinetic stability of ASDs on aging. Storage conditions including temperature and humidity could significantly affect the thermodynamicand kineticstabilityof ASDs.

Conclusion

When designing amorphous solid dispersions, it isrecommended that these thermodynamic, kinetic and environmental aspects should be completely investigatedand compared to establish rationale formulations for amorphous solid dispersions with high physical stability.

     

Continuous powder feeding for pharmaceutical solid dosage form manufacture: a short review

Abstract

There has been a noticeable shift from pharmaceutical batch processing towards a more continuous mode of manufacture for solid oral dosage forms. Continuous solid oral dose processes would not be possible in the absence of a highly accurate feeding system. The performance of feeders defines the content of formulations and is therefore a critical operation in continuous manufacturing of solid dosage forms. It was the purpose of this review to review the role of the initial powder feeding step in a continuous manufacturing process. Different feeding mechanisms are discussed with a particular emphasis on screw controlled loss in weight (LIW) feeding. The importance of understanding the physical properties of the raw materials and its impact on the feeding process is reviewed. Prior knowledge of materials provides an initial indication of how the powders will behave through processing and facilitates in the selection of the most suitable (i) feeder (capacity), (ii) feeding mechanism, and (iii) in the case of screw feeder – screw type. The studies identified in this review focus on the impact of material on powder feeding performance.     

Aqueous Solubility Enhancement Through Engineering of Binary Solid Composites: Pharmaceutical Applications

Limits to the aqueous solubility of emerging new chemical entities, as well as older drug molecules, represent a barrier to solid oral dosage form development. Numerous techniques are conventionally employed in aqueous solubility enhancement, although a universal strategy has proven elusive. Formation of binary solid composites, such as eutectics or amorphous solid dispersions, offers an alternative to traditional solubility enhancement techniques. The reality of these systems, however, is that very few examples have been made commercially available, ultimately stemming from a lack of understanding regarding structural and thermodynamic stability-indicating phenomena associated with higher-energy solid materials. In the present work, a comprehensive structurally based review of the fundamental solid-state properties of binary composite materials is presented. Specific emphasis is placed on current topics of research in the area of binary composite formation and the relationship to the underutilization of this technology with the pharmaceutical industry.     

Considerations in the Development of Physically Stable High Drug Load API- Polymer Amorphous Solid Dispersions in the Glassy State

In this Commentary, the authors expand on their earlier studies of the solid-state long-term isothermal crystallization of amorphous API from the glassy state in amorphous solid dispersions, and focus on the effects of polymer concentration, and its implications for producing high load API doses with minimum polymer concentration. After presenting an overview of the various mechanistic factors which influence the ability of polymers to inhibit API crystallization, including the chemical structure of the polymer relative to the API, the nature and strength of API-polymer noncovalent interactions, polymer molecular weight, impact on primary diffusive molecular mobility, as well as on secondary motions in the bulk and surface phases of the glass, we consider in more detail, the effects of polymer concentration. Here, we examine the factors that appear to allow relatively low polymer concentrations, i.e., less than 10%w/w polymer, to greatly reduce crystallization, including a focus on the heterogeneous structure of the glassy state, and the possible spatial distribution and concentration of polymer in certain key regions of the glass. This is followed by a review and analysis of examples in the recent literature focused on determining the minimum polymer concentration in an amorphous solid dispersion, capable of producing optimally stable high drug load amorphous dispersions.     

Physical ageing of amorphous polymeric excipients III. The possible consequences of ageing

Polymeric excipients are widely used in pharmaceutical technology, and most of them are amorphous or partly amorphous. A well-known property of such materials is that they undergo physical ageing, which is accompanied by volume and enthalpy relaxation and thus might result in severe structural changes in the polymer. This latter phenomenon can influence the properties of excipients and dosage forms, such as processability, mechanical strength and drug release. These alterations are of great significance in the case of solid dosage forms, as physical ageing occurs in the solid state of the polymer. Considering conventional tablets, the structural changes of fillers or binders along with storage can influence the above mentioned properties, while in the case of modified release tablets, matrix-forming and film-forming agents are to be taken into account, as well. In addition to this, by the examination of films, the presence of plasticizers is of great importance, as these materials can facilitate physical ageing via increasing the molecular mobility of the polymer. In the case of certain therapeutic systems (e.g. intrauterine devices), where the base of the dosage form is polymeric, significant changes are to be noted considering the drug release and physiological tolerability of the system.     

Crosslinked hydrogels—a promising class of insoluble solid molecular dispersion carriers for enhancing the delivery of poorly soluble drugs

Water-insoluble materials containing amorphous solid dispersions (ASD) are an emerging category of drug carriers which can effectively improve dissolution kinetics and kinetic solubility of poorly soluble drugs. ASDs based on water-insoluble crosslinked hydrogels have unique features in contrast to those based on conventional water-soluble and water-insoluble carriers. For example, solid molecular dispersions of poorly soluble drugs in poly(2-hydroxyethyl methacrylate) (PHEMA) can maintain a high level of supersaturation over a prolonged period of time via a feedback-controlled diffusion mechanism thus avoiding the initial surge of supersaturation followed by a sharp decline in drug concentration typically encountered with ASDs based on water-soluble polymers. The creation of both immediate- and controlled-release ASD dosage forms is also achievable with the PHEMA based hydrogels. So far, ASD systems based on glassy PHEMA have been shown to be very effective in retarding precipitation of amorphous drugs in the solid state to achieve a robust physical stability. This review summarizes recent research efforts in investigating the potential of developing crosslinked PHEMA hydrogels as a promising alternative to conventional water-soluble ASD carriers, and a related finding that the rate of supersaturation generation does affect the kinetic solubility profiles implications to hydrogel based ASDs.KEY WORDS: Amorphous solid dispersions, Crosslinked hydrogels, Poly(2-hydroxyethylmethacrylate), Supersaturation, Kinetic solubility     

Solid molecular dispersions of poorly water-soluble drugs in poly(2-hydroxyethyl methacrylate) hydrogels.

The applicability of cross-linked hydrogels in forming solid molecular dispersions to enhance the delivery of poorly soluble drugs has not been fully explored. The purpose of this study is to characterize physicochemical parameters affecting the formation of solid molecular dispersions of poorly water-soluble drugs in poly(2-hydroxyethyl methacrylate) (PHEMA) hydrogels and to investigate the effect of storage humidity levels on their physical stability. Samples were prepared by an equilibrium solvent loading process, using diclofenac sodium, piroxicam and naproxen as model drugs. These were characterized by X-ray diffraction (XRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR), as well as changes in the physical state during storage under different humidity conditions. The results show that a threshold drug loading level of about 30% exists in these solid molecular dispersions, above which amorphous to crystalline transition may occur. At any given drug loading, the onset of such change in physical state is accelerated at higher relative humidity levels during storage. The presence of hydrogen bonding between the polymer and the drug, as reflected in the observed FTIR band shifts, improves the compatibility between the drug and the polymer. This, together with a decreased mobility in the glassy polymer, helps to retard the crystallization event below the loading threshold. An increase in dissolution rate is also observed from the polymeric solid molecular dispersion as compared with that of the crystalline pure drug. These physicochemical results indicate that solid molecular dispersions based on PHEMA hydrogels can effectively enhance the dissolution and therefore should be potentially useful in improving the oral bioavailability of poorly water-soluble drugs.     

Supercritical carbon dioxide processing of active pharmaceutical ingredients for polymorphic control and for complex formation

Supercritical fluid technique have been exploited in extraction, separation and crystallization processes. In the field of pharmaceutics, supercritical carbon dioxide (scCO(2)) has been used for the purpose of micronization, polymorphic control, and preparation of solid dispersion and complexes. Particle design of active pharmaceutical ingredients is important to make the solid dosage forms with suitable physicochemical properties. Control of the characteristic properties of particles, such as size, shape, crystal structure and morphology is required to optimize the formulation. For solubility enhancement of poorly water-soluble drugs, preparation of the solid dispersion or the complexation with proper drugs or excipients should be a promising approach. This review focuses on aspects of polymorphic control and complexation behavior of active pharmaceutical ingredients by scCO(2) processing.     

Review article: mechanisms of drug release from tablets and capsules. 2. Dissolution

Optimal drug dissolution is crucial to the success of oral drug therapy. Slow dissolution has frequently been correlated with poor or erratic performance of oral dosage forms in vivo, and drugs of low aqueous solubility provide a major challenge to the designer of modern oral dosage forms. In this second of two reviews, we briefly describe the physical process of dissolution, the principal factors controlling drug dissolution from tablets and capsules, and the strategies that are utilized by pharmaceutical scientists to enhance drug dissolution of orally administered drugs.     

Drug–Polymer Solubility and Miscibility: Stability Consideration and Practical Challenges in Amorphous Solid Dispersion Development

Drug–polymer solid dispersion has been demonstrated as a feasible approach to formulate poorly water-soluble drugs in the amorphous form, for the enhancement of dissolution rate and bioperformance. The solubility (for crystalline drug) and miscibility (for amorphous drug) in the polymer are directly related to the stabilization of amorphous drug against crystallization. Therefore, it is important for pharmaceutical scientists to rationally assess solubility and miscibility in order to select the optimal formulation (e.g., polymer type, drug loading, etc.) and recommend storage conditions, with respect to maximizing the physical stability. This commentary attempts to discuss the concepts and implications of the drug–polymer solubility and miscibility on the stabilization of solid dispersions, review recent literatures, and propose some practical strategies for the evaluation and development of such systems utilizing a working diagram.     

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.     

Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process

Solid dispersions of felodipine were formulated with HPMC and surfactants by the conventional solvent evaporation (CSE) and supercritical anti-solvent precipitation (SAS) methods. The solid dispersion particles were characterized by particle size, zeta potential, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), powder X-ray diffraction (XRD), solubility and dissolution studies. The effects of the drug/polymer ratio and surfactants on the solubility of felodipine were also studied. The mean particle size of the solid dispersions was 200-250 nm; these had a relatively regular spherical shape with a narrow size distribution. The particle size of the solid dispersions from the CSE method increased at 1 h after dispersed in distilled water. However, the particle sizes of solid dispersions from the SAS process were maintained for 6 h due to the increased solubility of felodipine. The physical state of felodipine changed from crystalline to amorphous during the CSE and SAS processes, confirmed by DSC/XRD data. The equilibrium solubility of the felodipine solid dispersion prepared by the SAS process was 1.5-20 microg/ml, while the maximum solubility was 35-110 microg/ml. Moreover, the solubility of felodipine increased with decreasing drug/polymer ratio or increasing HCO-60 content. The solid dispersions from the SAS process showed a high dissolution rate of over 90% within 2 h. The SAS process system may be used to enhance solubility or to produce oral dosage forms with high dissolution rate.     

Current status of amorphous formulation and other special dosage forms as formulations for early clinical phases

Although most chemists in the pharmaceutical industry have a good understanding on favorable physicochemical properties for drug candidates, formulators must still deal with many challenging candidates. On the other hand, formulators are not allowed to spend much time on formulation development for early phases of the clinical studies. Thus, it is basically difficult to apply special dosage form technologies to the candidates for the first-in-human formulations. Despite the availability of numerous reviews on oral special dosage forms, information on their applicability as the early phase formulation has been limited. This article describes quick review on the oral special dosage forms that may be applied to the early clinical formulations, followed by discussion focused on the amorphous formulations, which still has relatively many issues to be proved for the general use. The major problems that inhibit the use of the amorphous formulation are difficulty in the manufacturing and the poor chemical/physical stability. Notably, the poor physical stability can be critical, because of not the poor stability itself but the difficulty in the timely evaluation in the preclinical developmental timeframes. Research directions of the amorphous formulations are suggested to utilize this promising technology without disturbing the preclinical developmental timelines. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2875–2885, 2009     

Melt extrusion with poorly soluble drugs

Melt extrusion (ME) over recent years has found widespread application as a viable drug delivery option in the drug development process. ME applications include taste masking, solid-state stability enhancement, sustained drug release and solubility enhancement. While ME can result in amorphous or crystalline solid dispersions depending upon several factors, solubility enhancement applications are centered around generating amorphous dispersions, primarily because of the free energy benefits they offer. In line with the purview of the current issue, this review assesses the utility of ME as a means of enhancing solubility of poorly soluble drugs/chemicals. The review describes major processing aspects of ME technology, definition and understanding of the amorphous state, manufacturability, analytical characterization and biopharmaceutical performance testing to better understand the strength and weakness of this formulation strategy for poorly soluble drugs. In addition, this paper highlights the potential advantages of employing a fusion of techniques, including pharmaceutical co-crystals and spray drying/solvent evaporation, facilitating the design of formulations of API exhibiting specific physico-chemical characteristics. Finally, the review presents some successful case studies of commercialized ME based products.     

Solid dispersions, part I: recent evolutions and future opportunities in manufacturing methods for dissolution rate enhancement of poorly water-soluble drugs

INTRODUCTION: In recent years, the number of active pharmaceutical ingredients with high therapeutic impact, but very low water solubility, has increased significantly. Thus, a great challenge for pharmaceutical technology is to create new formulations and efficient drug-delivery systems to overcome these dissolution problems. AREAS COVERED: Drug formulation in solid dispersions (SDs) is one of the most commonly used techniques for the dissolution rate enhancement of poorly water-soluble drugs. Generally, SDs can be defined as a dispersion of active ingredients in molecular, amorphous and/or microcrystalline forms into an inert carrier. This review covers literature which states that the dissolution enhancement of SDs is based on the fact that drugs in the nanoscale range, or in amorphous phase, dissolve faster and to a greater extent than micronized drug particles. This is in accordance to the Noyes-Whitney equation, while the wetting properties of the used polymer may also play an important role. EXPERT OPINION: The main factors why SD-based pharmaceutical products on the market are steadily increasing over the last few years are: the recent progress in various methods used for the preparation of SDs, the effect of evolved interactions in physical state of the drug and formulation stability during storage, the characterization of the physical state of the drug and the mechanism of dissolution rate enhancement.     

Molecular mobility-based estimation of the crystallization rates of amorphous nifedipine and phenobarbital in poly(vinylpyrrolidone) solid dispersions

The overall crystallization rates and mean relaxation times of amorphous nifedipine and phenobarbital in the presence of poly(vinylpyrrolidone) (PVP) were determined at various temperatures to gain further insight into the effect of molecular mobility on the crystallization rates of amorphous drugs and the possibility of predicting stability from their molecular mobility. Nifedipine-PVP (9:1 w/w) and phenobarbital-PVP (95:5 w/w) solid dispersions were prepared by melting and rapidly cooling mixtures of each drug and PVP. The amount of amorphous nifedipine remaining in the solid dispersion was calculated from the heat of crystallization,which was obtained by differential scanning calorimetry. The amount of amorphous phenobarbital remaining in the solid dispersion was estimated from the change in the heat capacity at its glass transition temperature (T(g)). The time required for the amount of amorphous drug remaining to fall to 90% (t(90)) was calculated from the profile of time versus the amount of amorphous drug remaining. The t(90) values for the solid dispersions studied were 100-1000 times longer than those of pure amorphous drugs when compared at the same temperature. Enthalpy relaxation of the amorphous drugs in the solid dispersions was reduced compared with that in the pure amorphous drugs, indicating that the molecular mobility of the amorphous drugs is reduced in the presence of PVP. The temperature dependence of mean relaxation time (tau) for the nifedipine-PVP solid dispersion was calculated using the Adam-Gibbs-Vogel equation. Parameters D and T(0) in this equation were estimated from the heating rate dependence of T(g). Similar temperature dependence was observed for t(90) and tau values of the solid dispersion, indicating that the information on the temperature dependence of the molecular mobility, along with the crystallization data obtained at around the T(g), are useful for estimating the t(90) of overall crystallization at temperatures below T(g) in the presence of excipients.     

Impact of Excipient Interactions on Solid Dosage Form Stability

Drug-excipient interactions in solid dosage forms can affect drug product stability in physical aspects such as organoleptic changes and dissolution slowdown, or chemically by causing drug degradation. Recent research has allowed the distinction in chemical instability resulting from direct drug-excipient interactions and from drug interactions with excipient impurities. A review of chemical instability in solid dosage forms highlights common mechanistic themes applicable to multiple degradation pathways. These common themes include the role of water and microenvironmental pH. In addition, special aspects of solid-state reactions with excipients and/or excipient impurities add to the complexity in understanding and modeling reaction pathways. This paper discusses mechanistic basis of known drug-excipient interactions with case studies and provides an overview of common underlying themes. Recent developments in the understanding of degradation pathways further impact methodologies used in the pharmaceutical industry for prospective stability assessment. This paper discusses these emerging aspects in terms of limitations of drug-excipient compatibility studies, emerging paradigms in accelerated stability testing, and application of mathematical modeling for prediction of drug product stability.