The Measurement of Small Quantities of Amorphous Material—Should We Be Considering the Rigid Amorphous Fraction?

Pharmaceutical Research -     

Impacts of Compression on Crystallization Behavior of Freeze‐Dried Amorphous Sucrose

An amorphous matrix comprised of sugar molecules is used as excipient and stabilizing agent for labile ingredients in the pharmaceutical industry. The amorphous sugar matrix is often compressed into a tablet form to reduce the volume and improve handling. Herein, the effect of compression on the crystallization behavior of an amorphous sucrose matrix was investigated. Amorphous sucrose samples were prepared by freeze‐drying and compressed under different conditions, followed by analyses by differential scanning calorimetry, isothermal crystallization tests, X‐ray powder diffractometry, Fourier transform infrared spectroscopy (FTIR), and gas pycnometry. The compressed sample had a lower crystallization temperature and a shorter induction period for isothermal crystallization, indicating that compression facilitates the formation of the critical nucleus of a sucrose crystal. Based on FTIR and molecular dynamics simulation results, the conformational distortion of sucrose molecules due to the compression appears to contribute to the increase in the free energy of the system, which leads to the facilitation of critical nucleus formation. An isothermal crystallization test indicated an increase in the growth rate of sucrose crystals by the compression. This can be attributed to the transformation of the microstructure from porous to nonporous, as the result of compression. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1452–1463, 2010     

Crystallization of Amorphous Solid Dispersions of Resveratrol during Preparation and Storage—Impact of Different Polymers

The objective of this study was to investigate intermolecular interactions between resveratrol and polymers in amorphous blends and to study the potential correlations between compound–polymer interactions, manufacturability, and stability of the amorphous system to crystallization during storage. Polymers included two grades of poly (vinylpyrrolidone) (PVP), Eudragit E100 (E100), hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), carboxymethyl cellulose acetate butyrate, and poly (acrylic acid) (PAA). Amorphous blends (“solid dispersions”) were prepared by dissolving both resveratrol and polymer in a solvent followed by rotary evaporation. Crystallinity was evaluated using X‐ray powder diffraction and was studied as a function of time. Mid‐infrared (IR) spectroscopy was used to investigate resveratrol–polymer interactions. Polymer influence on the crystallization behavior of resveratrol varied and could be correlated to the polymer structure, whereby polymers with good hydrogen bond acceptor groups performed better as crystallization inhibitors. Resveratrol–polymer hydrogen bonding interactions could be inferred from the IR spectra. Somewhat surprisingly, E100 and resveratrol showed evidence of an acid–base reaction, in addition to intermolecular hydrogen bonding interactions. PVP K29/32 appeared to form stronger hydrogen bond interactions with resveratrol relative to HPMC, HPMCAS, and PAA, consistent with acceptor group chemistry. Long‐term stability of the systems against crystallization suggested that stability is linked to the type and strength of intermolecular interactions present. whereby resveratrol blended with E100 and PVP K29/32 showed the greatest stability to crystallization. In conclusion, amorphous resveratrol is unstable and difficult to form, requiring the assistance of a polymeric crystallization inhibitor to facilitate the formation of an amorphous solid dispersion. Polymers effective at inhibiting crystallization were identified, and it is rationalized that their effectiveness is based on the type and strength of their intermolecular interactions with resveratrol.     

Optimization of a Raman Microscopy Technique to Efficiently Detect Amorphous–Amorphous Phase Separation in Freeze‐Dried Protein Formulations

A confocal Raman microscopic technique was optimized to more efficiently detect amorphous–amorphous phase separation in freeze‐dried protein formulations. A Renishaw Raman inVia confocal microscope was used to collect 100–200 μm line maps (2 μm step size) of freeze‐dried protein–excipient formulations. At each point across the line map, the composition was evaluated from the intensity of the nonoverlapping peaks representative of each component. Collection aperture, scan time, and line map length significantly contributed to the phase‐separation analysis, whereas different sample preparation methods did not affect the analysis. Using the optimized parameters (i.e., large aperture 5 s scan time, 200 μm line map), phase separation was successfully detected in binary polymer formulations and was comparable to the previously developed Raman method. However, the previous method required 2.5 h/sample, whereas the optimized method only requires 0.5 h/sample. Phase separation was detected in the following protein–excipient formulations: lysozyme–trehalose (1:1), lysozyme–isomaltose (1:1), β‐lactoglobulin–dextran (1:1), β‐lactoglobulin–dextran (1:3), and β‐lactoglobulin–trehalose (1:1). Phase separation was not detected in lysozyme–sucrose (1:1) and β‐lactoglobulin–sucrose (1:1) formulations. The optimized method successfully detected phase separation in several protein formulations, where phase separation was previously suspected, and promised to be a useful tool for detection of phase separation in amorphous therapeutic formulations. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2749–2758, 2014     

Stable and Fast-Dissolving Amorphous Drug Composites Preparation via Impregnation of Neusilin® UFL2

A promising approach to increase the aqueous solubility, hence the bioavailability, of poorly water-soluble drugs is to convert them into their amorphous state through impregnation into mesoporous silica. Unfortunately, mesoporous silica is not yet available in bulk quantities due to high manufacturing costs. In this work, feasibility of using a commercially available cost-effective mesoporous fine grade Neusilin^® UFL2 to prepare amorphous drug composites of 2 model poorly soluble drugs, fenofibrate and itraconazole, is established. In contrast to fluidized-bed spray-impregnation, only mixing and drying steps are required. Complimentary assessment using X-ray powder diffraction, differential scanning calorimetry, and Raman spectroscopy confirmed drug within the composites to be amorphous at as high as 30% drug loading both after formation and after 3 months of storage at 40°C and 75% relative humidity. Amorphous drug recrystallization was completely suppressed due to the confinement effect due to the Neusilin^®. The amorphous drug composites resulted in higher apparent solubility and faster dissolution rate of the model drugs as compared to their crystalline counterpart, confirmed by United States Pharmacopeia II dissolution and ultraviolet surface dissolution imaging. Overall, stable, high drug-loaded fast-dissolving amorphous drug composites preparation using Neusilin^® UFL2 is demonstrated as a promising approach to enhance solubility of poorly soluble drugs.     

Rapid Assessment of Homogeneity and Stability of Amorphous Solid Dispersions by Atomic Force Microscopy—From Bench to Batch

Purpose

To verify the robustness and fundamental value of Atomic Force Microscopy (AFM) and AFM-based assays to rapidly examine the molecular homogeneity and physical stability of amorphous solid dispersions on Hot-Melt-Extrudates.

Methods

Amorphous solid dispersions were prepared with a Hot-Melt Extruder (HME) and profiled by Raman Microscopy and AFM following a sequential analytical routine (Multi-Scale-Imaging-of-Miscibiliy (MIMix)). Extrudates were analyzed before and after incubation at elevated temperature and humidity. The data were compared with published results as collected on miniaturized melt models. The value of molecular phase separation rates for long term stability prediction was assessed.

Results

Data recorded on the extrudates are consistent with those published, and they can be compared side by side. Such direct data comparisons allow the identification of possible sources of extrudate heterogeneities. The surface roughness analysis of fracture-exposed interfaces is a novel quantitative way to trace on the nanometer scale the efficiencies of differently conducted HME-processes. Molecular phase separation rates are shown to be relevant for long term stability predictions.

Conclusions

The AFM-based assessment of API:excipient combinations is a robust method to rapidly identify miscible and stable solid dispersions in a routine manner. It provides a novel analytical tool for the optimization of HME processes.     

How Much Surface Coating of Hydrophobic Azithromycin Is Sufficient to Prevent Moisture-Induced Decrease in Aerosolisation of Hygroscopic Amorphous Colistin Powder?

Aerosolisation performance of hygroscopic particles of colistin could be compromised at elevated humidity due to increased capillary forces. Co-spray drying colistin with a hydrophobic drug is known to provide a protective coating on the composite particle surfaces against moisture-induced reduction in aerosolisation performance; however, the effects of component ratio on surface coating quality and powder aerosolisation at elevated relative humidities are unknown. In this study, we have systematically examined the effects of mass ratio of hydrophobic azithromycin on surface coating quality and aerosolisation performance of the co-spray dried composite particles. Four combination formulations with varying drug ratios were prepared by co-spray drying drug solutions. Both of the drugs in each combination formulation had similar in vitro deposition profiles, suggesting that each composite particle comprises two drugs in the designed mass ratio, which is supported by X-ray photoelectron spectroscopy (XPS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) data. XPS and ToF-SIMS measurements also revealed that 50% by weight (or 35% by molecular fraction) of azithromycin in the formulation provided a near complete coating of 96.5% (molar fraction) on the composite particle surface, which is sufficient to prevent moisture-induced reduction in fine particle fraction (FPF)recovered and FPFemitted. Higher azithromycin content did not increase coating coverage, while contents of azithromycin lower than 20% w/w did not totally prevent the negative effects of humidity on aerosolisation performance. This study has highlighted that a critical amount of azithromycin is required to sufficiently coat the colistin particles for short-term protection against moisture.     

Dissolution Kinetics of Nifedipine—Ionizable Polymer Amorphous Solid Dispersion: Comparison Between Bicarbonate and Phosphate Buffers

Pharmaceutical Research - The intestinal fluid pH is maintained by the bicarbonate buffer system that shows unique properties regarding drug dissolution. Nevertheless, current compendial...     

Estimation of Drug–Polymer Miscibility and Solubility in Amorphous Solid Dispersions Using Experimentally Determined Interaction Parameters

Purpose  The amorphous form of a drug may provide enhanced solubility, dissolution rate, and bioavailability but will also potentially crystallize over time. Miscible polymeric additives provide a means to increase physical stability. Understanding the miscibility of drug–polymer systems is of interest to optimize the formulation of such systems. The purpose of this work was to develop experimental models which allow for more quantitative estimates of the thermodynamics of mixing amorphous drugs with glassy polymers. Materials and Methods  The thermodynamics of mixing several amorphous drugs with amorphous polymers was estimated by coupling solution theory with experimental data. The entropy of mixing was estimated using Flory–Huggins lattice theory. The enthalpy of mixing and any deviations from the entropy as predicted by Flory–Huggins lattice theory were estimated using two separate experimental techniques; (1) melting point depression of the crystalline drug in the presence of the amorphous polymer was measured using differential scanning calorimetry and (2) determination of the solubility of the drug in 1-ethyl-2-pyrrolidone. The estimated activity coefficient was used to calculate the free energy of mixing of the drugs in the polymers and the corresponding solubility. Results  Mixtures previously reported as miscible showed various degrees of melting point depression while systems reported as immiscible or partially miscible showed little or no melting point depression. The solubility of several compounds in 1-ethyl-2-pyrrolidone predicts that most drugs have a rather low solubility in poly(vinylpyrrolidone). Conclusions  Miscibility of various drugs with polymers can be explored by coupling solution theories with experimental data. These approximations provide insight into the physical stability of drug–polymer mixtures and the thermodynamic driving force for crystallization.     

Solubility Advantage of Amorphous Pharmaceuticals,Part 3: Is Maximum Solubility Advantage Experimentally Attainable and Sustainable?

A method is described for screening compounds that inhibit crystallization in solution to enable more accurate measurement of amorphous drug solubility. Three polymers [polyvinylpyrrolidone, hydroxypropyl methylcellulose, and hydroxypropyl methylcellulose acetate succinate (HPMCAS)] were screened for their ability to inhibit the crystallization of neat amorphous drugs during measurement of solubility of the amorphous form in water. Among the polymers evaluated, HPMCAS was found to be most promising. The use of HPMCAS provided an “apparent solubility” of amorphous drugs that was closer to the theoretically calculated values. With danazol, agreement was essentially quantitative, and for griseofulvin and iopanoic acid, agreement was within a factor of two; these maximum concentrations were sustained for a period of 40–90 xsmin. Dynamic light scattering of filtered samples (0.22 µ) revealed the presence of colloidal drug–polymer assemblies in solution (100–150 nm). The supernatant resulting from this centrifugation gradually decreased in concentration, but remained supersaturated with respect to crystalline drug for several hours. Thus, HPMCAS has been shown to be a useful additive in dissolution media to allow a more accurate determination of the solubility of fast crystallizing neat amorphous drugs, at least for the drugs studied, and it should also serve to retard crystallization in vivo and therefore, facilitate improved bioavailability. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4349–4356, 2011     

What is the True Solubility Advantage for Amorphous Pharmaceuticals?

Purpose. To evaluate the magnitude of the solubility advantage foramorphous pharmaceutical materials when compared to their crystallinecounterparts.Methods. The thermal properties of several drugs in their amorphousand crystalline states were determined using differential scanningcalorimetry. From these properties the solubility advantage for theamorphous form was predicted as a function of temperature using a simplethermodynamic analysis. These predictions were compared to theresults of experimental measurements of the aqueous solubilities of theamorphous and crystalline forms of the drugs at several temperatures.Results. By treating each amorphous drug as either an equilibriumsupercooled liquid or a pseudo-equilibrium glass, the solubilityadvantage compared to the most stable crystalline form was predicted to bebetween 10 and 1600 fold. The measured solubility advantage wasusually considerably less than this, and for one compound studied indetail its temperature dependence was also less than predicted. It wascalculated that even for partially amorphous materials the apparentsolubility enhancement (theoretical or measured) is likely to influencein-vitro and in-vivo dissolution behavior.Conclusions. Amorphous pharmaceuticals are markedly more solublethan their crystalline counterparts, however, their experimental solubility advantage is typically less than that predicted from simplethermodynamic considerations. This appears to be the result of difficulties indetermining the solubility of amorphous materials under trueequilibrium conditions. Simple thermodynamic predictions can provide a useful indication of the theoretical maximum solubility advantage foramorphous pharmaceuticals, which directly reflects the driving forcefor their initial dissolution.     

Stabilized Amorphous State of Ibuprofen by Co‐Spray Drying With Mesoporous SBA‐15 to Enhance Dissolution Properties

A novel formulation process via co‐spray drying ibuprofen (IBU) with mesoporous SBA‐15 submicron particles exhibited excellence in production of stable amorphous IBU with significantly enhanced dissolution rate. With drug loading of IBU/SBA‐15 ratio being 50:50 (w/w) or below, most drug molecules were entrapped inside the straight mesoporous channels via the co‐spray drying and the morphology of SBA‐15 submicron particles remained unchanged. IBU confined inside the mesoporous structure was in the amorphous state shown by PXRD and DSC measurements. The amorphous state of IBU in the solid dispersion showed remarkable stability when subject to stress test condition of 40°C/75% RH in open pans for 12 months. The uniform pore walls were believed to prevent the re‐crystallization of the homogeneously dispersed drug molecules inside the mesoporous channels with confined nanospace. The dissolution rate of IBU from the co‐spray‐dried solid dispersion was significantly enhanced to achieve a rapid release. Even after the accelerated stability test, the rapid drug release property was well preserved. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1997–2007, 2010     

Amorphous Water-Soluble Cyclodextrin Derivatives: 2-Hydroxyethyl, 3-Hydroxypropyl, 2-Hydroxyisobutyl,and Carboxamidomethyl Derivatives of β-Cyclodextrin

The pharmaceutical usefulness of natural, crystalline cyclodextrins can be improved by chemical conversions into water-soluble, amorphous mixtures of their derivatives. Reaction of -cyclodextrin with 2-chloroethanol, 3-chloropropanol, isobutylene oxide, or iodoacetamide yielded the title compounds. Distributions of the substitution degree were close to symmetrical and relatively narrow. The average substitution degrees increased with the amount of alkylating reagent used in the preparation. The number of components (half-width of distribution) increased with increasing average substitution degree. Further, distributions of the substitution degree were measured in glucose derivatives after hydrolysis of 2-hydroxyethyl, 2-hydroxypropyl, and 2-hydroxyisobutyl--cyclodextrin. The results show an uneven distribution of substitutents around the cyclodextrins, suggesting that growth of oligoglycol side chains and/or clustering of substituents on one glucose residue occurs.     

Solid-State 13C Nuclear Magnetic Resonance Spectroscopic Study on Amorphous Solid Complexes of Tolbutamide with 2-Hydroxypropyl-α-and -β-Cyclodextrins

Purpose. The objective of the study was to obtain structural information of inclusion complexes of tolbutamide with HP-- and --cyclo-dextrins in amorphous state. Methods. The solid complexes of tolbutamide with HP-- and --CyDs in molar ratios of 1:1 and 1:2 (guest:host) were prepared by the spray-drying method, and their interactions were investigated by solid-state ^I3C nuclear magnetic resonance (NMR) spectroscopy. Results. The solid 1:1 and l:2tolbutamide/HP-CyD complexes showed halo pattern on the powder X-ray diffractogram and no thermal change in DSC curves, indicating they are in an amorphous state.¹³C NMR signals of the butyl moiety were broader than those of the phenyl moiety in the HP--CyD solid complex, whereas the phenyl moiety showed significantly broader signals than the butyl moiety in the HP--CyD solid complex. As temperature increased, signals of the phenyl carbons became markedly sharper, whereas the butyl carbons only sharpen slightly in the HP-d-CyD complex. In contrast, signals of the butyl carbons became significantly sharper whereas those of phenyl carbons only slightly changed in the HP--CyD complex. Conclusions. Solid state ¹³C NMR spectroscopic studies indicated that the butyl moiety of tolbutamide is predominantly included in the HP--CyD cavity, whereas the phenyl moiety in the HP--CyD cavity in amorphous complexes.     

Possibilities and Limiting Factors for the Use of Dissolution as a Quality Control Tool to Detect Presence of Crystallinity for Amorphous Solid Dispersions: An Experimental and Modeling Investigation

In this article, experiments on tablets containing a model compound, grazoprevir, were conducted to explore how media selection for a quality control dissolution method can influence the sensitivity for the dissolution method toward drug crystallinity detection in an amorphous solid dispersion formulation. The experiment shows that under ideal nonsink conditions with respect to crystalline solubility, dissolution can indeed be predictive of crystallinity in the formulation. However, the limit of detection for crystallinity with quality control dissolution can change based on inherent variabilities in the drug product. In addition, it is demonstrated that the method's sensitivity and accuracy might be reduced if the crystalline particles are sufficiently small with respect to the solid dispersion particles. To further demonstrate the limits of the dissolution method, a dissolution model was also explored to simulate and predict the sensitivity of the dissolution response toward crystallinity based on solubility in the media and particle size of the crystals.     

The Measurement of the β/α Anomer Composition Within Amorphous Lactose Prepared by Spray and Freeze Drying Using a Simple 1H-NMR Method

Purpose  

Reports of the anomeric composition of amorphous lactose are rare and state a highly variable range of composition (between 0% and 60% w/w β content). We aimed to develop a quantitative measurement by ¹H-NMR of α and β anomer content in amorphous lactose produced by different production methods.     

Amorphous solid dispersions and nanocrystal technologies for poorly water-soluble drug delivery – An update

Poor water-solubility remains a typical property of drug candidates in pharmaceutical development pipelines today. Various processes have been developed to increase the solubility, dissolution rate, and bioavailability of these active ingredients belonging to biopharmaceutical classification system (BCS) II and IV classifications. Since the early 2000s, nanocrystal delivery and amorphous solid dispersions are more established techniques to overcome the limitations of poorly-water soluble drugs in FDA available products. This article provides an updated review of nanocrystal and amorphous solid dispersion techniques primarily for orally delivered medicaments. The thermodynamic and kinetic theories relative to these technologies are presented along with marketed product evaluations and a survey of commercially relevant scientific literature.     

Co-Spray Dried Carbohydrate Microparticles: Crystallisation Delay/Inhibition and Improved Aerosolization Characteristics Through the Incorporation of Hydroxypropyl-β-cyclodextrin with Amorphous Raffinose or Trehalose

Pharmaceutical Research - To formulate and investigate the physicochemical properties, physical stability and aerosolization characteristics of nanoporous/nanoparticulate microparticles (NPMPs)...     

Rifampin Stability and Solution Concentration Enhancement Through Amorphous Solid Dispersion in Cellulose ω-Carboxyalkanoate Matrices

Tuberculosis (TB) is a deadly infectious disease; approximately 2 billion people are currently latently infected with the causative agent Mycobacterium tuberculosis. Approximately 8 million new active cases and 2 million deaths due to TB are recorded annually.¹ Rifampin (Rif) is a vital first-line TB treatment drug. Its effectiveness is hampered by the high dose required (600 mg 1×/day) and by its moderate, variable bioavailability. These issues can be explained by Rif instability at gastric pH, limited solubility at neutral pH, polymorphism, and stimulation of its own metabolism. To overcome these obstacles, we developed new cellulose-based oral drug delivery systems aiming to increase and make more consistent Rif solubility and bioavailability. Amorphous solid dispersions (ASDs) of Rif with cellulose ω-carboxyalkanoates (cellulose acetate suberate, cellulose acetate propionate adipate, and cellulose acetate butyrate sebacate) were prepared and compared with crystalline Rif (negative) and carboxymethyl cellulose acetate butyrate ASD (positive) controls. Cellulose ω-carboxyalkanoate ASDs prevented acid-catalyzed degradation in conditions mimicking the acidic stomach and provided complete release of intact Rif at intestinal pH. Rif incorporation into ASD in these novel cellulose derivative matrices creates the potential for convenient, robust, consistent, and high Rif oral bioavailability for treatment of TB.