Impact of Micellar Surfactant on Supersaturation and Insight into Solubilization Mechanisms in Supersaturated Solutions of Atazanavir

Purpose

The goals of this study were to determine: 1) the impact of surfactants on the “amorphous solubility”; 2) the thermodynamic supersaturation in the presence of surfactant micelles; 3) the mechanism of solute solubilization by surfactant micelles in supersaturated solutions.

Methods

The crystalline and amorphous solubility of atazanavir was determined in the presence of varying concentrations of micellar sodium dodecyl sulfate (SDS). Flux measurements, using a side-by-side diffusion cell, were employed to determine the free and micellar-bound drug concentrations. The solubilization mechanism as a function of atazanavir concentration was probed using fluorescence spectroscopy. Pulsed gradient spin-echo proton nuclear magnetic resonance (PGSE-NMR) spectroscopy was used to determine the change in micelle size with a change in drug concentration.

Results

Changes in the micelle/water partition coefficient, K _m/w , as a function of atazanavir concentration led to erroneous estimates of the supersaturation when using concentration ratios. In contrast, determining the free drug concentration using flux measurements enabled improved determination of the thermodynamic supersaturation in the presence of micelles. Fluorescence spectroscopic studies suggested that K _m/w changed based on the location of atazanavir solubilization which in turn changed with concentration. Thus, at a concentration equivalent to the crystalline solubility, atazanavir is solubilized by adsorption at the micelle corona, whereas in highly supersaturated solutions it is also solubilized in the micellar core. This difference in solubilization mechanism can lead to a breakdown in the prediction of amorphous solubility in the presence of SDS as well as challenges with determining supersaturation. PGSE-NMR suggested that the size of the SDS micelle is not impacted at the crystalline solubility of the drug but increases when the drug concentration reaches the amorphous solubility, in agreement with the proposed changes in solubilization mechanism.

Conclusions

Micellar solubilization of atazanavir is complex, with the solubilization mechanism changing with differences in the degree of (super)saturation. This can result in erroneous predictions of the amorphous solubility and thermodynamic supersaturation in the presence of solubilizing additives. This in turn hinders understanding of the driving force for phase transformations and membrane transport, which is essential to better understand supersaturating dosage forms.

     

Dissolution Performance of High Drug Loading Celecoxib Amorphous Solid Dispersions Formulated with Polymer Combinations

Purpose

The aims of this study were twofold. First, to evaluate the effectiveness of selected polymers in inhibiting solution crystallization of celecoxib. Second, to compare the release rate and crystallization tendency of celecoxib amorphous solid dispersions (ASDs) formulated with a single polymer, or binary polymer combinations.

Methods

The effectiveness of polymers, polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) or HPMC acetate succinate (HPMCAS), in maintaining supersaturation of celecoxib solutions was evaluated by performing nucleation induction time measurements. Crystallization kinetics of ASD suspensions were monitored using Raman spectroscopy. Dissolution experiments were carried out under non-sink conditions.

Results

Pure amorphous celecoxib crystallized rapidly through both matrix and solution pathways. Matrix and solution crystallization was inhibited when celecoxib was molecularly mixed with a polymer, resulting in release of the drug to form supersaturated solutions. Cellulosic polymers were more effective than PVP in maintaining supersaturation. Combining a cellulosic polymer and PVP enabled improved drug release and stability to crystallization.

Conclusions

Inclusion of an effective solution crystallization inhibitor as a minor component in ternary dispersions resulted in prolonged supersaturation following dissolution. This study shows the feasibility of formulation strategies for ASDs where a major polymer component is used to achieve one key property e.g. release, while a minor polymer component is added to prevent crystallization.

     

Characterization of Supersaturated Danazol Solutions – Impact of Polymers on Solution Properties and Phase Transitions

Purpose

Excipients are essential for solubility enhancing formulations. Hence it is important to understand how additives impact key solution properties, particularly when supersaturated solutions are generated by dissolution of the solubility enhancing formulation. Herein, the impact of different concentrations of dissolved polymers on the thermodynamic and kinetic properties of supersaturated solutions of danazol were investigated.

Methods

A variety of experimental techniques was used, including nanoparticle tracking analysis, fluorescence and ultraviolet spectroscopy and flux measurements to characterize the solution phase behavior.

Results

Neither the crystalline nor amorphous solubility of danazol was impacted by common amorphous solid dispersion polymers, polyvinylpyrrolidone, hydroxypropylmethyl cellulose (HPMC) or HPMC-acetate succinate. Consequently, the maximum membrane transport rate was limited only by the amorphous solubility, and not by the presence of the polymers. The polymers were able to inhibit crystallization to some extent at concentrations as low as 1 μg/mL, with the maximum effectiveness being reached at 10 μg/mL. Aqueous danazol solutions formed a drug-rich phase with a mean size of 250 nm when the concentration exceeded the amorphous solubility, and the polymers modified the surface properties of this drug-rich phase.

Conclusions

The phase behavior of supersaturated solutions is complex and the kinetics of phase transformations can be substantially modified by polymeric additives present at low concentrations. However, fortunately, these additives do not appear to impact the bulk thermodynamic properties of the solution, thus enabling supersaturated solutions, which provide enhanced membrane transport relative to saturated solutions to be generated.

     

Polymer/Amorphous Salt Solid Dispersions of Ciprofloxacin

Purpose

To improve the pharmaceutical properties of amorphous ciprofloxacin (CIP) succinate salts via formulation as polymer/amorphous salt solid dispersions (ASSDs).

Methods

ASSDs consisting of an amorphous CIP/succinic acid 1:1 or 2:1 salt dispersed in PVP or Soluplus were produced by spray drying and ball milling. The solid state characteristics, miscibility, stability, solubility and passive transmembrane permeability of the ASSDs were then examined.

Results

The ASSDs had higher glass transition and crystallization temperatures than the corresponding amorphous succinate salts, and were also more stable during long-term stability studies. The results of inverse gas chromatography and thermal analysis indicated that the salts and polymers form a miscible mixture. The solubility of the pure drug in water and biorelevant media was significantly increased by all of the formulations. The permeability of the ASSDs did not differ significantly from that of the amorphous CIP succinate salts, however all samples were less permeable than the pure crystalline drug.

Conclusions

The formulation of amorphous CIP succinate salts as ASSDs with polymer improved their long-term stability, but did not significantly affect their solubility or permeability.

     

Leaching of Lopinavir Amorphous Solid Dispersions in Acidic Media

Purpose

Amorphous solid dispersions (ASDs) formulated with acid-insoluble (enteric) polymers form suspensions in acidic media where the polymer is largely insoluble. However, a small amount of drug can dissolve and a supersaturated solution may be generated. The goal of this study was to gain insight into the leaching mechanisms of both drug and polymer from the suspended particles, studying the impact of solution additives such as surfactants.

Methods

ASDs were prepared by spray drying lopinavir (LPV) with an enteric polymer, either hydroxypropylmethylcellulose acetate succinate (HPMCAS) or hydroxypropylmethylcellulose phthalate (HPMCP). Four surfactants and a suspending agent were added to the liquid media to evaluate the effect of these excipients on leaching. pH 3 and pH 5 buffers were used to investigate the effect of pH.

Results

The extent of drug leaching from the amorphous formulation was proportional to the crystalline solubility of the drug in the same medium. All surfactants promoted solubilization of LPV with the exception of poloxamer and sodium dodecyl sulfate-HPMCP combinations. A small amount of polymer ionization significantly enhanced LPV leaching in solutions containing an ionic surfactant.

Conclusions

The mechanism of enhanced leaching appeared to be solubilization, with the apparent supersaturation remaining the same for systems containing the same polymer.

     

Elucidation of Compression-Induced Surface Crystallization in Amorphous Tablets Using Sum Frequency Generation (SFG) Microscopy

Purpose

To investigate the effect of compression on the crystallization behavior in amorphous tablets using sum frequency generation (SFG) microscopy imaging and more established analytical methods.

Method

Tablets containing neat amorphous griseofulvin with/without excipients (silica, hydroxypropyl methylcellulose acetate succinate (HPMCAS), microcrystalline cellulose (MCC) and polyethylene glycol (PEG)) were prepared. They were analyzed upon preparation and storage using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, scanning electron microscopy (SEM) and SFG microscopy.

Results

Compression-induced crystallization occurred predominantly on the surface of the neat amorphous griseofulvin tablets, with minimal crystallinity being detected in the core of the tablets. The presence of various types of excipients was not able to mitigate the compression-induced surface crystallization of the amorphous griseofulvin tablets. However, the excipients affected the crystallization rate of amorphous griseofulvin in the core of the tablet upon compression and storage.

Conclusions

SFG microscopy can be used in combination with ATR-FTIR spectroscopy and SEM to understand the crystallization behaviour of amorphous tablets upon compression and storage. When selecting excipients for amorphous formulations, it is important to consider the effect of the excipients on the physical stability of the amorphous formulations.

     

Targeted Intestinal Delivery of Supersaturated Itraconazole for Improved Oral Absorption

Purpose

To investigate the use of Carbopol® 974P as a stabilizing agent for supersaturated levels of itraconazole (ITZ) in neutral pH aqueous media and the resultant effects on oral absorption of ITZ.

Methods

Carbopol® 974P was incorporated into an EUDRAGIT® L 100-55 carrier matrix at concentrations of 20% and 40% based on polymer weight with the aim of prolonging supersaturated ITZ release from the enteric matrix. Amorphous solid dispersions of ITZ in EUDRAGIT® L 100-55 containing either 20% or 40% Carbopol® 974P were produced by hot-melt extrusion (HME). Solid state analysis of these compositions was performed using differential scanning calorimetry and qualitative energy dispersive X-ray spectroscopy. Dissolution analysis was conducted using a pH change method. Oral absorption of ITZ was evaluated in male Sprague–Dawley rats.

Results

Solid state analysis demonstrated that the extruded compositions were entirely amorphous and homogenous with respect to drug distribution in the polymer matrix. Dissolution analysis revealed that the addition of Carbopol® 974P to the EUDRAGIT® L 100-55 carrier system functioned to prolong the release of supersaturated levels of ITZ from the EUDRAGIT® L 100-55 matrix following an acidic-to-neutral pH transition. In vivo evaluation of ITZ absorption revealed that the addition of Carbopol® 974P substantially reduced the absorption variability seen with the EUDRAGIT® L 100-55 carrier system. In addition, the 20% Carbopol® 974P formulation exhibited a five-fold improvement in absorption over our initially reported ITZ particulate dispersion compositions that limited supersaturation of ITZ primarily to the stomach.

Conclusions

The results of this study strongly suggest that substantial improvements in oral antifungal therapy with ITZ can be achieved via intestinal targeting and polymeric stabilization of supersaturation.

     

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.

     

Exploring Molecular Speciation and Crystallization Mechanism of Amorphous 2-Phenylamino Nicotinic Acid

Purpose

Molecular understanding of phase stability and transition of the amorphous state helps in formulation and manufacturing of poorly-soluble drugs. Crystallization of a model compound, 2-phenylamino nicotinic acid (2PNA), from the amorphous state was studied using solid-state analytical methods. Our previous report suggests that 2PNA molecules mainly develop intermolecular –COOH???pyridine N (acid-pyridine) interactions in the amorphous state. In the current study, the molecular speciation is explored with regard to the phase transition from the amorphous to the crystalline state.

Methods

Using spectroscopic techniques, the molecular interactions and structural evolvement during the recrystallization from the glassy state were investigated.

Results

The results unveiled that the structurally heterogeneous amorphous state contains acid-pyridine aggregates – either as hydrogen-bonded neutral molecules or as zwitterions – as well as a population of carboxylic acid dimers. Phase transition from the amorphous state results in crystal structures composed of carboxylic acid dimer (acid-acid) synthon or acid-pyridine chains depending on the crystallization conditions employed.

Conclusions

The study underlines the structural evolvement, as well as its impact on the metastability, of amorphous samples from local, supramolecular assemblies to long-range intermolecular ordering through crystallization.

     

Gelatin Nano-coating for Inhibiting Surface Crystallization of Amorphous Drugs

Purpose

Inhibit the fast surface crystallization of amorphous drugs with gelatin nano-coatings.

Methods

The free surface of amorphous films of indomethacin or nifedipine was coated by a gelatin solution (type A or B) and dried. The coating’s effect on surface crystallization was evaluated. Coating thickness was estimated from mass change after coating.

Results

For indomethacin (weak acid, pK_a?=?4.5), a gelatin coating of either type deposited at pH 5 and 10 inhibited its fast surface crystal growth. The coating thickness was 20?±?10 nm. A gelatin coating deposited at pH 3, however, provided no protective effect. These results suggest that an effective gelatin coating does not require that the drug and the polymer have opposite charges. The ineffective pH 3 coating might reflect the poor wetting of indomethacin’s neutral, hydrophobic surface by the coating solution. For nifedipine (weak base, pK_a?=?2.6), a gelatin coating of either type deposited at pH 5 inhibited its fast surface crystal growth.

Conclusions

Gelatin nano-coatings can be conveniently applied to amorphous drugs from solution to inhibit fast surface crystallization. Unlike strong polyelectrolyte coatings, a protective gelatin coating does not require strict pairing of opposite charges. This could make gelatin coating a versatile, pharmaceutically acceptable coating for stabilizing amorphous drugs.

     

Evaluation of the Crystallization Tendency of Commercially Available Amorphous Tacrolimus Formulations Exposed to Different Stress Conditions

Purpose

Tacrolimus, an immunosuppressant, is a poorly water soluble compound whereby the commercially available capsule formulations contain the drug in amorphous form. The goal of this study was to evaluate the robustness of the innovator product and five generic formulations to crystallization following storage at stress conditions.

Methods

Products were purchased from a pharmacy and stored at 40°C/75% relative humidity (RH), open dish conditions. Crystallinity was determined using X-ray diffraction. The quantity of the ingredients in the formulations were determined using different approaches and the various factors that might cause instability in the formulations were studied.

Results

After 4 weeks of open dish storage at 40°C/75% RH, one of the generic formulations showed evidence of tacrolimus crystallization. Further investigations revealed batch-to-batch variations in crystallization tendency with the extent of crystallinity varying between 50 and 100% for different batches. Crystallization was also observed at lower storage temperatures (30°C) when the RH was maintained at 75%. It was found that crystallization could be induced in a model formulation by wet granulating an ethanolic solution of the drug with lactose and drying at 60–70°C followed by exposure to stress conditions.

Conclusions

It seems probable that the generic that was susceptible to crystallization contains amorphous drug physically mixed with polymeric excipients, rather than as an amorphous solid dispersion. This study highlights the importance of considering the manufacturing process on the stability of the resultant amorphous product.

     

Characterization of Solid Dispersion of Itraconazole Prepared by Solubilization in Concentrated Aqueous Solutions of Weak Organic Acids and Drying

Purpose

The purpose of this study was to develop an amorphous solid dispersion (SD) of an extremely water-insoluble and very weakly basic drug, itraconazole (ITZ), by interaction with weak organic acids and then drying that would enhance dissolution rate of drug and physical stability of formulation.

Methods

Aqueous solubility of ITZ in concentrated solutions of weak organic acids, such as glutaric, tartaric, malic and citric acid, was determined. Solutions with high drug solubility were dried using vacuum oven and the resulting SDs having 2 to 20% drug load were characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The dissolution of SDs was initially studied in 250 mL of 0.1 N HCl (pH 1.1), and any undissolved solids were collected and analyzed by PXRD. The pH of the dissolution medium was then changed from 1.1 to 5.5, particle size of precipitates were measured, and drug concentrations in solution were determined by filtration through membrane filters of varying pore sizes.

Results

The aqueous solubility of ITZ was greatly enhanced in presence of weak acids. While the solubility of ITZ in water was ~4 ng/ mL, it increased to 25–40 mg per g of solution at 25°C and 200 mg per g of solution at 65°C at a high acid concentration leading to extremely high solubilization. PXRD of SDs indicated that ITZ was present in the amorphous form, wherein the acid formed a partially crystalline matrix. ATR-FTIR results showed possible weak interactions, such as hydrogen bonding, between drug and acid but there was no salt formation. SDs formed highly supersaturated solutions at pH 1.1 and had superior dissolution rate as compared to amorphous drug and physical mixtures of drug and acids. Following the change in pH from 1.1 to 5.5, ITZ precipitated as mostly nanoparticles, providing high surface area for relatively rapid redissolution.

Conclusions

A method of highly solubilizing an extremely water-insoluble drug, ITZ, in aqueous media and converting it into an amorphous form in a physically stable SD was successfully investigated. The dissolution rate and the extent of supersaturation of the drug in dissolution media improved greatly, and any precipitate formed at high pH had very small particle size.

     

Meal Effects Confound Attempts to Counteract Rabeprazole-Induced Hypochlorhydria Decreases in Atazanavir Absorption

Purpose

Clinically relevant pharmacokinetic interactions exist between gastric acid-reducing agents and certain weakly basic drugs that rely on acidic environments for optimal oral absorption. In this study, we examine whether the administration of betaine hydrochloride under fed conditions can enhance the absorption of atazanavir, an HIV-1 protease inhibitor, during pharmacologically-induced hypochlorhydria.

Methods

In this randomized, single-dose, 3 period, crossover study healthy volunteers received ritonavir-boosted atazanavir (atazanavir/ritonavir 300/100 mg) alone, following pretreatment with the proton pump inhibitor rabeprazole (20 mg twice daily), and with 1500 mg of betaine HCl after rabeprazole pretreatment. Atazanavir was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule.

Results

Pretreatment with rabeprazole resulted in significant reductions in atazanavir C_max (p?<?0.01) and AUC_0-last (p?<?0.001) (71 and 70%, respectively), and modest decreases in ritonavir C_max and AUC_last (p?<?0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATV C_max and 12% of AUC_last lost due to rabeprazole.

Conclusions

The co-administration of rabeprazole with atazanavir resulted in significant decreases in atazanavir exposure. The addition of betaine HCl did not sufficiently mitigate the loss of ATV exposure observed during RAB-induced hypochlorhydria. Meal effects lead to a marked difference in the outcome of betaine HCl on atazanavir exposure than we previously reported for dasatanib under fasting conditions.

     

Synergistic Effect of Polyvinyl Alcohol and Copovidone in Itraconazole Amorphous Solid Dispersions

Purpose

The first objective is to evaluate the feasibility of melt-extruding polyvinyl alcohol-based amorphous solid dispersions for oral drug delivery. The second objective is to investigate the miscibility between polyvinyl alcohol 4-88 and copovidone, and to characterize the properties of ternary itraconazole amorphous solid dispersions comprising both polymers.

Methods

Samples were prepared using a co-rotating, twin-screw extruder. A solution precipitation study was conducted to compare the precipitation inhibition of polyvinyl alcohol against other commonly used polymers for amorphous solid dispersions. Miscibility between polyvinyl alcohol 4-88 and copovidone was determined using DSC and XRD analyses. All extrudates were characterized using DSC, XRD, and non-sink dissolution.

Results

Polyvinyl alcohol demonstrated the highest capacity for inhibiting the precipitation of itraconazole. Itraconazole was found to be more soluble in copovidone (>30%) than in polyvinyl alcohol 4-88 (<5%) in binary extrudates. Polyvinyl alcohol and copovidone are miscible when the proportion of polyvinyl alcohol 4-88 does not exceed 30% (w/w). Compared to binary extrudates, the ternary extrudate demonstrated a higher degree of supersaturation and more sustained supersaturation of itraconazole in purified water and phosphate buffer pH 6.8 solution.

Conclusion

As a surface-active material, polyvinyl alcohol was effective in inhibiting precipitation of itraconazole in aqueous media. Solubility of itraconazole in polyvinyl alcohol in solid state was limited because of the high polarity of the polymer. Ternary systems comprising a mixture of polyvinyl alcohol and copovidone demonstrated better supersaturation in aqueous media than binary systems. Ternary systems benefited from both the high solubilizing capacity of copovidone and high precipitation inhibition capacity of polyvinyl alcohol.

     

Probing Influence of Solvent on Polymorphic Transformation of Carbamazepine Using Electrospray Technology

Purpose

The objective of the current work was to investigate the influence of electrospray technology using various solvents on polymorphic transformations of carbamazepine (CBZ). CBZ was taken as a model drug for electrospray crystallization owing to its well investigated polymorphic forms.

Methods

Saturated CBZ solutions (methanol, ethanol, and 2-propanol) were electrosprayed at 20 kV to obtain CBZ crystals. The electrosprayed crystals from methanol (MCBZ), ethanol (ECBZ), and 2-propanol (PCBZ) were characterized by powder X-ray diffractometry, Fourier-transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy, equilibrium solubility, intrinsic dissolution rate, and stability study.

Results

MCBZ exhibited mixture of form I and II of CBZ, whereas mixture of form I, II, and III of CBZ was observed in case of ECBZ. Further, PCBZ contained mixture of form II, III, and IV of CBZ. The order in which reduction in saturation solubility and intrinsic dissolution rate was observed, it can be represented as MCBZ > PCBZ > ECBZ > unprocessed CBZ. Electrospray technology induced polymorphic transformations in CBZ crystals. The said polymorphic transformations were influenced by solvent properties along with an electric charge.

Conclusion

Thus electrospray crystallization, a continuous pharmaceutical manufacturing technique, can serve as an alternative for crystallization of API with an ability to modify their physicochemical properties.

     

Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds

Purpose

To develop a small-scale set-up to rapidly and accurately determine the intrinsic dissolution rate (IDR) and apparent solubility of poorly water-soluble compounds.

Methods

The IDR and apparent solubility (S_app) were measured in fasted state simulated intestinal fluid (FaSSIF) for six model compounds using wet-milled controlled suspensions (1.0% (w/w) PVP and 0.2% (w/w) SDS) and the μDISS Profiler. Particle size distribution was measured using a Zetasizer and the total surface area was calculated making use of the density of the compound. Powder and disc dissolution were performed and compared to the IDR of the controlled suspensions.

Results

The IDR values obtained from the controlled suspensions were in excellent agreement with IDR from disc measurements. The method used low amount of compound (μg-scale) and the experiments were completed within a few minutes. The IDR values ranged from 0.2–70.6 μg/min/cm² and the IDR/S_app ratio ranged from 0.015 to 0.23. This ratio was used to indicate particle size sensitivity on intestinal concentrations reached for poorly water-soluble compounds.

Conclusions

The established method is a new, desirable tool that provides the means for rapid and highly accurate measurements of the IDR and apparent solubility in biorelevant dissolution media. The IDR/S_app is proposed as a measure of particle size sensitivity when significant solubilization may occur.

     

Effects of Moisture-Induced Crystallization on the Aerosol Performance of Spray Dried Amorphous Ciprofloxacin Powder Formulations

Purpose

This study aims to investigate the influence of different storage humidity conditions on crystallization and aerosol performance of inhalable spray dried amorphous powder formulations (Ciprofloxacin hydrochloride as the model drug).

Methods

The spray dried samples were stored at 20%, 55% and 75% relative humidity (RH). Crystallinity was monitored by Powder X-ray diffraction (PXRD), and particle morphology was measured by scanning electron microscopy (SEM) and atomic force microscopy (AFM). Aerosol performance was evaluated using a multi-stage liquid impinger (MSLI).

Results

PXRD diffractograms showed the spray dried Ciprofloxacin stored at 20% RH for three weeks were amorphous; whereas those stored at 55% RH and 75% RH started crystallizing after one hour. Fine particle fraction (FPF) of the particles was improved from 28% to 42% after storage at 55% RH for three days. Such improvement was attributed to the crystallization of amorphous powders, which led to increased particle roughness and reduced particulate contact area, as visualized by SEM and quantified by AFM. A linear relationship was observed between degree of crystallinity/crystallite size and FPF (R²?=?0.94 and R²?=?0.96, respectively). However, deterioration in aerosol performance was observed after storage at 75% RH due to formation of inter-particulate liquid/solid bridges, as confirmed by SEM.

Conclusions

This study provides a fundamental understanding in moisture-induced physical and aerosol instability of the spray dried powder formulations.

     

The Combined Use of Imaging Approaches to Assess Drug Release from Multicomponent Solid Dispersions

Purpose

Imaging methods were used as tools to provide an understanding of phenomena that occur during dissolution experiments, and ultimately to select the best ratio of two polymers in a matrix in terms of enhancement of the dissolution rate and prevention of crystallization during dissolution.

Methods

Magnetic resonance imaging, ATR-FTIR spectroscopic imaging and Raman mapping have been used to study the release mechanism of a poorly water soluble drug, aprepitant, from multicomponent amorphous solid dispersions. Solid dispersions were prepared based on the combination of two selected polymers - Soluplus, as a solubilizer, and PVP, as a dissolution enhancer. Formulations were prepared in a ratio of Soluplus:PVP 1:10, 1:5, 1:3, and 1:1, in order to obtain favorable properties of the polymer carrier.

Results

The crystallization of aprepitant during dissolution has occurred to a varying degree in the polymer ratios 1:10, 1:5, and 1:3, but the increasing presence of Soluplus in the formulation delayed the onset of crystallization. The Soluplus:PVP 1:1 solid dispersion proved to be the best matrix studied, combining the abilities of both polymers in a synergistic manner.

Conclusions

Aprepitant dissolution rate has been significantly enhanced. This study highlights the benefits of combining imaging methods in order to understand the release process.

     

A Strategy for Co-former Selection to Design Stable Co-amorphous Formations Based on Physicochemical Properties of Non-steroidal Inflammatory Drugs

Purpose

This study aimed to investigate the physicochemical factors contributing to stable co-amorphous formations and to design a co-former selection strategy.

Methods

Non-steroidal inflammatory drugs were used as main components and/or co-formers. Physical mixtures of the materials were melted. Co-amorphization was characterized by the inhibition effect of the co-former on crystallization of the main component from the undercooled melt. The contribution of physicochemical factors to the co-amorphous formation was analyzed by multivariate analysis. Co-amorphous samples prepared by melting were subjected to thermal and spectroscopic analyses and the isothermal crystallization test.

Results

Naproxen (NAP) was employed as the main component having a rapid crystallization tendency. Some materials used as the co-former inhibited the crystallization of amorphous NAP; decreasing melting temperatures of the components was an indicator of co-amorphization. The contribution of some physicochemical features (e.g., crystallization tendency, glass transition temperature (Tg)/melting temperature and molecular flexibility) of the co-formers to a co-amorphous formation was suggested by multivariate analysis. Deviation of the glass transition temperature from the theoretical value and changes in the infrared spectra of the co-amorphous samples were correlated with intermolecular interaction. The crystallization behaviors of the co-amorphous samples depended on their Tg.

Conclusions

The results showed a relationship between stable co-amorphous formation and the physicochemical features of the components, which should inform efficient co-former selection to design stable co-amorphous formations.

     

Estimating Maximal <Emphasis Type="BoldItalic">In Vitro</Emphasis> Skin Permeation Flux from Studies Using Non-sink Receptor Phase Conditions

Purpose

This study explored the impact of non-sink receptor conditions on the in vitro skin permeation test (IVPT) and sought to estimate equivalent sink condition IVPT data.

Methods

Simulated diffusion model and experimental IVPT data were generated for ethyl salicylate across human epidermal membranes in Franz diffusion cells using six different receptor phases, with a 10 fold variation in ethyl salicylate solubility.

Results

Both simulated and experimental IVPT – time profiles were markedly affected by receptor phase solubility and receptor sampling rates. Similar sink condition equivalent estimated maximum fluxes were obtained by nonlinear regression and adjustment of linear regression estimates of steady state flux for relative saturation of the receptor phase over time for the four receptor phases in which the ethyl salicylate was relatively soluble. The markedly lower steady - state fluxes found for the other two phases in which ethyl salicylate was less soluble was attributed to an aqueous solution boundary layer effect.

Conclusions

Non-sink receptor phase IVPT data can be used to derive equivalent sink receptor phase IVPT data provided the receptor phase solubility and hydrodynamics are sufficient to minimise the impact of aqueous diffusion layers on IVPT data.