In Situ Cocrystallization via Spray Drying with Polymer as a Strategy to Prevent Cocrystal Dissociation.

The aim of the present study was to investigate how different polymers affect the dissociation of cocrystals prepared by co-spray-drying active pharmaceutical ingredient (API), coformer, and polymer. Diclofenac acid-l-proline cocrystal (DPCC) was selected in this study as a model cocrystal due to its previously reported poor physical stability in a high-humidity environment. Polymers investigated include polyvinylpyrrolidone (PVP), poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA), hydroxypropyl methyl cellulose, hydroxypropylmethylcellulose acetate succinate, ethyl cellulose, and Eudragit L-100. Terahertz Raman spectroscopy (THz Raman) and powder X-ray diffraction (PXRD) were used to monitor the cocrystal dissociation rate in a high-humidity environment. A Raman probe was used in situ to monitor the extent of the dissociation of DPCC and DPCC in crystalline solid dispersions (CSDs) with polymer when exposed to pH 6.8 phosphate buffer and water. The solubility of DPCC and solid dispersions of DPCC in pH 6.8 phosphate buffer and water was also measured. The dissociation of DPCC was water-mediated, and more than 60% of DPCC dissociated in 18 h at 40 °C and 95% RH. Interestingly, the physical stability of the cocrystal was effectively improved by producing CSDs with polymers. The inclusion of just 1 wt % polymer in a CSD with DPCC protected the cocrystal from dissociation over 18 h under the same conditions. Furthermore, the CSD with PVPVA was still partially stable, and the CSD with PVP was stable (undissociated) after 7 days. The superior stability of DPCC in CSDs with PVP and PVPVA was also demonstrated when systems were exposed to water or pH 6.8 phosphate buffer and resulted in higher dynamic solubility of the CSDs compared to DPCC alone. The improvement in physical stability of the cocrystal in CSDs was thought to be due to an efficient mixing between polymer and cocrystal at the molecular level provided by spray drying and in situ gelling of polymer. It is hypothesized that polymer chains could undergo gelling in situ and form a physical barrier, preventing cocrystal interaction with water, which contributes to slowing down the water-mediated dissociation.

Spray Encapsulation as a Formulation Strategy for Drug-Based Room Temperature Ionic Liquids: Exploiting Drug-Polymer Immiscibility to Enable Processing for Solid Dosage Forms.

Active pharmaceutical ingredient (API)-based ionic liquids (API-ILs) present an exciting new paradigm for the formulation of poorly water-soluble drugs. In this study, a model room temperature API-IL (1-butyl-3-methyl imidazolium ibuprofenate) was demonstrated to be not just highly soluble but fully miscible and hence have effectively unlimited solubility in water, compared to 0.021 mg mL-1 solubility for the ibuprofen API. Solutions of the API-IL were found to be stable for up to 2 years, indicating that they have the potential to offer thermodynamic stability upon release, avoiding in vivo recrystallization issues that can limit the bioavailability of amorphous solid dispersions (ASDs) and some high-energy crystalline forms. The ibuprofen API-IL was successfully spray-dried into a polymer carrier in loadings of up to 75% w/w in order to transform it into a solid powder suitable for oral solid dosage (OSD) formulation. From modulated differential scanning calorimetry, hot-stage microscopy, powder X-ray diffraction, and attenuated total reflectance Fourier transform infrared spectroscopy measurements, the mechanism by which this high loading was achieved is based on the immiscibility between the polymer and API-IL, with the polymer encapsulating the phase-separated API-IL. Dissolution studies showed that solidification of the API-IL into microcapsules by spray drying in this manner had no detrimental effect on release characteristics. Failure to dissolve crystalline API forms into the polymer matrix eliminates the solubility enhancement of ASDs but not for highly soluble or fully miscible API-ILs. Furthermore, miscible API-IL/polymer dispersions at high loadings were found to possess less-favorable physical properties because of melting point depression, resulting, in some cases, in a failure to form a viable powder. As such, microencapsulated API-ILs at high loadings in immiscible or low-miscibility polymers that have solubility enhancement of the API-IL form, while providing solid powders for processing, represent a promising new platform for the formulation of poorly soluble compounds as OSDs.

A Comparative Study on the Performance of Inert and Functionalized Spheres Coated with Solid Dispersions Made of Two Structurally Related Antifungal Drugs.

Fluid bed coating offers potential advantages as a formulation platform for amorphous solid dispersions (ASDs) of poorly soluble drugs, being a one-step manufacturing process which could reduce the risk of phase separation associated with multiple step manufacturing approaches. However, the impact of the physicochemical nature of nonpareil carriers on the properties and drug release from the ASDs has not been studied in detail. In this work, tartaric acid (TAP) and microcrystalline cellulose (CEL) spheres were chosen as examples of functional and inert beads, respectively. Two structurally related triazole antifungals, itraconazole (ITR) and posaconazole (POS), were chosen as model drugs. Solid-state investigations revealed that the fluidized bed process result in both types of spheres uniformly coated with ITR and POS ASDs based on Eudragit L100-55 (EUD). A single glass transition temperature (Tg) was determined for each of the ASDs. Infrared studies suggested the presence of a weak interaction between POS and TAP, which translated into premature release of POS from the POS/EUD ASD coated TAP spheres in FaSSGF and subsequently lower POS cumulative release in comparison to the ASD coated on CEL beads. High resolution investigations of morphological and compositional changes during dissolution, using scanning electron microscopy and atomic force microscopy coupled with nanoscale thermal investigation, revealed that crystallization of the drug from the ASDs was induced during dissolution when TAP spheres were used as carriers. In contrast, ASDs coated on CEL underwent phase separation and drug-rich nanospecies were formed in the matrix due to the solubility gap between the drug and EUD in FaSSIF. This study demonstrates that properties of carrier for the ASD fundamentally affect the drug release properties and the proper selection of carrier beads is critical to ensure product quality.

Comparative Study of Different Methods for the Prediction of Drug-Polymer Solubility.

In this study, a comparison of different methods to predict drug-polymer solubility was carried out on binary systems consisting of five model drugs (paracetamol, chloramphenicol, celecoxib, indomethacin, and felodipine) and polyvinylpyrrolidone/vinyl acetate copolymers (PVP/VA) of different monomer weight ratios. The drug-polymer solubility at 25 °C was predicted using the Flory-Huggins model, from data obtained at elevated temperature using thermal analysis methods based on the recrystallization of a supersaturated amorphous solid dispersion and two variations of the melting point depression method. These predictions were compared with the solubility in the low molecular weight liquid analogues of the PVP/VA copolymer (N-vinylpyrrolidone and vinyl acetate). The predicted solubilities at 25 °C varied considerably depending on the method used. However, the three thermal analysis methods ranked the predicted solubilities in the same order, except for the felodipine-PVP system. Furthermore, the magnitude of the predicted solubilities from the recrystallization method and melting point depression method correlated well with the estimates based on the solubility in the liquid analogues, which suggests that this method can be used as an initial screening tool if a liquid analogue is available. The learnings of this important comparative study provided general guidance for the selection of the most suitable method(s) for the screening of drug-polymer solubility.

In vitro and in vivo characterisation of PEG-lipid-based micellar complexes of salmon calcitonin for pulmonary delivery.

PURPOSE: To investigate DSPE-PEG(2000)-based micellar formulations of salmon calcitonin (sCT) for their ability to improve pulmonary delivery. METHODS: Micelles were characterised by DLS and (31)P-NMR spectroscopy. Stability against sCT degrading peptidases, trypsin, α-chymotrypsin and neutrophil elastase as well as their influence on transepithelial absorption was investigated in vitro. In vivo performance of sCT micelles was studied in an experimental model of intratracheal aerosolisation into rats. RESULTS: Micelles with a mean hydrodynamic diameter of 12 nm spontaneously assembled, when a total concentration of 0.02 mM of PEG-lipid and sCT (at 1:1 molar ratio) was exceeded. Nuclear magnetic resonance confirmed the presence of small micellar structures. The micellar formulation showed increased stability against enzymatic digestion. In vitro studies also showed that sCT micelles were able to enhance transepithelial absorption. Data obtained from in vivo experiments provided evidence of significantly (P < 0.05) higher mean plasma concentrations of sCT, after inhalation of micelles compared to sCT solution, at 60 and 90 min, a significantly higher AUC (inf) and a relative bioavailability of 160 ± 55% when compared to plain sCT solution. CONCLUSIONS: The herein described PEG-lipid micelles are promising carriers for enhanced pulmonary delivery of sCT.

A comparison of spray drying and milling in the production of amorphous dispersions of sulfathiazole/polyvinylpyrrolidone and sulfadimidine/polyvinylpyrrolidone.

Formulations containing amorphous active pharmaceutical ingredients (APIs) present great potential to overcome problems of limited bioavailability of poorly soluble APIs. In this paper, we directly compare for the first time spray drying and milling as methods to produce amorphous dispersions for two binary systems (poorly soluble API)/excipient: sulfathiazole (STZ)/polyvinylpyrrolidone (PVP) and sulfadimidine (SDM)/PVP. The coprocessed mixtures were characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and intrinsic dissolution tests. PXRD and DSC confirmed that homogeneous glassy solutions (mixture with a single glass transition) of STZ/PVP were obtained for 0.05 ≤ X(PVP) (PVP weight fraction) < 1 by spray drying and for 0.6 ≤ X(PVP) < 1 by milling (at 400 rpm), and homogeneous glassy solutions of SDM/PVP were obtained for 0 < X(PVP) < 1 by spray drying and for 0.7 ≤ X(PVP) < 1 by milling. For these amorphous composites, the value of T(g) for a particular API/PVP ratio did not depend on the processing technique used. Variation of T(g) versus concentration of PVP was monotonic for all the systems and matched values predicted by the Gordon-Taylor equation indicating that there are no strong interactions between the drugs and PVP. The fact that amorphous SDM can be obtained on spray drying but not amorphous STZ could not be anticipated from the thermodynamic driving force of crystallization, but may be due to the lower molecular mobility of amorphous SDM compared to amorphous STZ. The solubility of the crystalline APIs in PVP was determined and the activities of the two APIs were fitted to the Flory-Huggins model. Comparable values of the Flory-Huggins interaction parameter (χ) were determined for the two systems (χ = -1.8 for SDM, χ = -1.5 for STZ) indicating that the two APIs have similar miscibility with PVP. Zones of stability and instability of the amorphous dispersions as a function of composition and temperature were obtained from the Flory-Huggins theory and the Gordon-Taylor equation and were found to be comparable for the two APIs. Intrinsic dissolution studies in aqueous media revealed that dissolution rates increased in the following order: physical mix of unprocessed materials < physical mix of processed material < coprocessed materials. This last result showed that production of amorphous dispersions by co-milling can significantly enhance the dissolution of poorly soluble drugs to a similar magnitude as co-spray dried systems.

Evaluation of HPßCD-PEG microparticles for salmon calcitonin administration via pulmonary delivery.

For therapeutic peptides, the lung represents an attractive, noninvasive route into the bloodstream. To achieve optimal bioavailability and control their fast rate of absorption, peptides can be protected by coprocessing with polymers such as polyethylene glycol (PEG). Here, we formulated and characterized salmon calcitonin (sCT)-loaded microparticles using linear or branched PEG (L-PEG or B-PEG) and hydroxypropyl-beta-cyclodextrin (HPßCD) for pulmonary administration. Mixtures of sCT, L-PEG or B-PEG and HPßCD were co-spray dried. Based on the particle properties, the best PEG:HPßCD ratio was 1:1 w:w for both PEGs. In the sCT-loaded particles, the L-PEG was more crystalline than B-PEG. Thus, L-PEG-based particles had lower surface free energy and better aerodynamic behavior than B-PEG-based particles. However, B-PEG-based particles provided better protection against chemical degradation of sCT. A decrease in sCT permeability, measured across Calu-3 bronchial epithelial monolayers, occurred when the PEG and HPßCD concentrations were both 1.6 wt %. This was attributed to an increase in buffer viscosity, caused by the two excipients. sCT pharmacokinetic profiles in Wistar rats were evaluated using a 2-compartment model after iv injection or lung insufflation. The maximal sCT plasma concentration was reached within 3 min following nebulization of sCT solution. L-PEG and B-PEG-based microparticles were able to increase T(max) to 20 ± 1 min and 18 ± 8 min, respectively. Furthermore, sCT absolute bioavailability after L-PEG-based microparticle aerosolization at 100 µg/kg was 2.3 times greater than for the nebulized sCT solution.

Design and characterisation of an amorphous formulation of nifedipine for the treatment of autonomic dysreflexia.

OBJECTIVES: Current treatment for autonomic dysreflexia (AD) involves rupturing a liquid-filled soft capsule of nifedipine to aid rapid drug release and absorption, however, this application is not covered under the manufacturer's license. The objective of the current work was to design a rapidly dissolving solid dosage formulation for the treatment of AD as an alternative to the off-license "bite and swallow" use of currently available commercial products. METHODS: Amorphous solid dispersions (ASDs) of nifedipine were prepared by spray-drying using three different polymers: hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus), at a 15% w/w drug loading and were formulated and compressed into tablets. Dissolution testing was performed in the paddle dissolution apparatus using either a monophasic or biphasic medium. KEY FINDINGS: The PVP-nifedipine ASD tablets exhibited rapid dissolution, with 35% of the total nifedipine dose dissolving within 15 min in the monophasic dissolution medium. The HPMC-nifedipine ASD exhibited a very slow dissolution, while the Solupus-nifedipine system exhibited no nifedipine release over 120 min. When tested in the biphasic dissolution medium, the PVP-nifedipine ASD tablets exhibited a release profile comparable to that of the pre-split/ruptured nifedipine soft capsule product. CONCLUSIONS: This study demonstrates that a nifedipine-PVP ASD is a promising formulation strategy in the treatment of AD.

Image-based characterization of powder flow to predict the success of pharmaceutical minitablet manufacturing.

Powder flowability plays an important role in die filling during tablet manufacturing. The present study introduces a novel small-scale measuring technique for powder flow. Based on image analysis, the flow was defined depending on the variation of luminous intensity and the movement of powder inside the measurement cuvette. Using quantities around 100 mg it was possible to characterize a wide range of common pharmaceutical powders, especially in distinguishing subtle differences in flow caused by minor changes in samples characteristics. The method was compared with powder rheometry, which is widely used in the pharmaceutical literature, and showed a significant improvement in predicting the success of pharmaceutical minitablet manufacture (d = 5 mm). Tablet weight variation (RSD) was defined as the most efficient way to assess relevant powder flow behaviour in tablet production when using the novel device. The proposed method was distinguished from others by its ability to classify different grades of microcrystalline cellulose in the die-filling process. Subsequently, eight common pharmaceutical powders, both excipients and APIs, were properly ranked as a function of flowability based on their physical properties. The method showed a high repeatability, with a relative standard deviation not more than 10%.

Amorphous solid dispersions of ketoprofen and poly-vinyl polymers prepared via electrospraying and spray drying: A comparison of particle characteristics and performance.

The purpose of this work was to compare the particle characteristics and dissolution performance of amorphous solid dispersions (ASDs) of ketoprofen and vinyl-pyrrolidone based polymers prepared using electrospraying and spray drying methods. Solution characteristics (surface tension, viscosity and conductivity) were determined for ethanolic solutions containing different vinyl-pyrrolidone based polymers (PVP and PVPVA) and different ketoprofen to polymer mass ratios. The only statistically significant difference in solution properties between PVP and PVPVA systems was electrical conductivity. The higher conductivity in PVP-containing solutions resulted in smaller, more spherical particles than the equivalent formulations prepared with PVPVA when processed via electrospraying. Electrospraying resulted in powders with higher specific surface area, smaller mean particle size, and narrower particle size distribution relative to the spray-dried material. Amorphisation of ketoprofen via both processes was confirmed using pXRD, DSC and FTIR. Although the specific surface area of the electrosprayed powder was higher than the equivalent spray-dried system, this did not translate into a faster dissolution rate at pH 1.2 but did lead to a faster surface moisture adsorption rate at various relative humidities. The flowability of the powder produced via the electrospraying process is poor compared to the equivalent powder produced via spray drying, which may cause challenges in downstream processing. While the ASD powder produced via electrospraying had a smaller particle size and narrower size distribution compared to equivalent spray-dried ASD, further refinement in terms of a final formulation is needed to translate this benefit into an improved dissolution rate in the case of ketoprofen.

Engineering of pharmaceutical cocrystals in an excipient matrix: Spray drying versus hot melt extrusion.

The comparison of spray drying versus hot melt extrusion (HME) in order to formulate amorphous solid dispersions has been widely studied. However, to the best of our knowledge, the use of both techniques to form cocrystals within a carrier excipient has not previously been compared. The combination of ibuprofen (IBU) and isonicotinamide (INA) in a 1:1 M ratio was used as a model cocrystal. A range of pharmaceutical excipients was selected for processing - mannitol, xylitol, Soluplus and PVP K15. The ratio of cocrystal components to excipient was altered to assess the ratios at which cocrystal formation occurs during spray drying and HME. Hansen Solubility Parameter (HSP) and the difference in HSP between the cocrystal and excipient (ΔHSP) was employed as a tool to predict cocrystal formation. During spray drying, when the difference in HSP between the cocrystal and the excipient was large, as in the case of mannitol (ΔHSP of 18.3 MPa0.5), a large amount of excipient (up to 50%) could be incorporated without altering the integrity of the cocrystal, whereas for Soluplus and PVP K15, where the ΔHSP was 2.1 and 1.6 MPa0.5 respectively, the IBU:INA cocrystal alone was only formed at a very low weight ratio of excipient, i.e. cocrystal:excipient 90:10. Remarkably different results were obtained in HME. In the case of Soluplus and PVP K15, a mixture of cocrystal with single components (IBU and INA) was obtained even when only 10% excipient was included. In conclusion, in order to reduce the number of unit operations required to produce a final pharmaceutical product, spray drying showed higher feasibility over HME to produce cocrystals within a carrier excipient.

Physicochemical and in vitro deposition properties of salbutamol sulphate/ipratropium bromide and salbutamol sulphate/excipient spray dried mixtures for use in dry powder inhalers.

The physicochemical and aerodynamic properties of spray dried powders of the drug/drug mixture salbutamol sulphate/ipratropium bromide were investigated. The in vitro deposition properties of spray dried salbutamol sulphate and the spray dried drug/excipient mixtures salbutamol sulphate/lactose and salbutamol sulphate/PEG were also determined. Spray drying ipratropium bromide monohydrate resulted in a crystalline material from both aqueous and ethanolic solution. The product spray dried from aqueous solution consisted mainly of ipratropium bromide anhydrous. There was evidence of the presence of another polymorphic form of ipratropium bromide. When spray dried from ethanolic solution the physicochemical characterisation suggested the presence of an ipratropium bromide solvate with some anhydrous ipratropium bromide. Co-spray drying salbutamol sulphate with ipratropium bromide resulted in amorphous composites, regardless of solvent used. Particles were spherical and of a size suitable for inhalation. Twin impinger studies showed an increase in the fine particle fraction (FPF) of spray dried salbutamol sulphate compared to micronised salbutamol sulphate. Co-spray dried salbutamol sulphate:ipratropium bromide 10:1 and 5:1 systems also showed an increase in FPF compared to micronised salbutamol sulphate. Most co-spray dried salbutamol sulphate/excipient systems investigated demonstrated FPFs greater than that of micronised drug alone. The exceptions to this were systems containing PEG 4000 20% or PEG 20,000 40% both of which had FPFs not significantly different from micronised salbutamol sulphate. These two systems were crystalline unlike most of the other spray dried composites examined which were amorphous in nature.

Materials and methods for delivery of biological drugs.

Biological drugs generated via recombinant techniques are uniquely positioned due to their high potency and high selectivity of action. The major drawback of this class of therapeutics, however, is their poor stability upon oral administration and during subsequent circulation. As a result, biological drugs have very low bioavailability and short therapeutic half-lives. Fortunately, tools of chemistry and biotechnology have been developed into an elaborate arsenal, which can be applied to improve the pharmacokinetics of biological drugs. Depot-type release systems are available to achieve sustained release of drugs over time. Conjugation to synthetic or biological polymers affords long circulating formulations. Administration of biological drugs through non-parenteral routes shows excellent performance and the first products have reached the market. This Review presents the main accomplishments in this field and illustrates the materials and methods behind existing and upcoming successful formulations and delivery strategies for biological drugs.

Comparative evaluation of rivastigmine permeation from a transdermal system in the Franz cell using synthetic membranes and pig ear skin with in vivo-in vitro correlation.

In the present study, in vitro permeation experiments in a Franz diffusion cell were performed using different synthetic polymeric membranes and pig ear skin to evaluate a rivastigmine (RV) transdermal drug delivery system. In vitro-in vivo correlations (IVIVC) were examined to determine the best model membrane. In vitro permeation studies across different synthetic membranes and skin were performed for the Exelon(®) Patch (which contains RV), and the results were compared. Deconvolution of bioavailability data using the Wagner-Nelson method enabled the fraction of RV absorbed to be determined and a point-to-point IVIVC to be established. The synthetic membrane, Strat-M™, showed a RV permeation profile similar to that obtained with pig ear skin (R(2)=0.920). Studies with Strat-M™ resulted in a good and linear IVIVC (R(2)=0.991) when compared with other synthetic membranes that showed R(2) values less than 0.90. The R(2) for pig ear skin was 0.982. Strat-M™ membrane was the only synthetic membrane that adequately simulated skin barrier performance and therefore it can be considered to be a suitable alternative to human or animal skin in evaluating transdermal drug transport, potentially reducing the number of studies requiring human or animal samples.

Physicochemical evaluation of PVP-thiazide diuretic interactions in co-spray-dried composites--analysis of glass transition composition relationships.

The aim of this study was to evaluate the possible interactions in the solid state between the thiazide diuretics: bendroflumethiazide (BFMT), hydroflumethiazide (HFMT) and hydrochlorothiazide (HCT) and polyvinylpyrrolidone (PVP) following processing. The glass transition temperatures (T(g)s) of a range of binary co-spray-dried PVP-thiazide composites were determined and compared to the predictions of the Gordon-Taylor, Fox, Couchman-Karasz, Kwei and Schneider equations. The solid composites of the thiazide diuretics and PVP were prepared by a spray drying technique. Properties of composites were determined with the use of helium pycnometry and FTIR spectroscopy. For many systems studied the experimentally detected T(g)s exhibited large positive deviations when compared with the values predicted by the Gordon-Taylor, Fox and Couchman-Karasz equations. The data was better fitted by the Schneider equation consistent with a drug-polymer interaction. FTIR analysis revealed that strong hydrogen bonding between the sulphonamide groups of the thiazide diuretics and the PVP molecule was responsible for the increase in the T(g)s. Additionally, in the case of BFMT-PVP composites, an interaction between the phenyl group and polymer ring was apparent. Glass transition-composition behaviour for amorphous drug-PVP composites deviated from the predictions of the commonly used Gordon-Taylor equation. Deviations were consistent with interactions between the components in the amorphous mixtures. The Schneider equation may be successfully applied to fit the Tg-composition profiles obtained, where other models fail to give good predictions.

Moisture diffusion and permeability characteristics of hydroxypropylmethylcellulose and hard gelatin capsules.

The primary objective of this paper is to compare the sorption characteristics of hydroxypropylmethylcellulose (HPMC) and hard gelatin (HG) capsules and their ability to protect capsule contents. Moisture sorption and desorption isotherms for empty HPMC and HG capsules have been investigated using dynamic vapour sorption (DVS) at 25°C. All sorption studies were analysed using the Young-Nelson model equations which distinguishes three moisture sorption types: monolayer adsorption moisture, condensation and absorption. Water vapour diffusion coefficients (D), solubility (S) and permeability (P) parameters of the capsule shells were calculated. ANOVA was performed with the Tukey comparison test to analyse the effect of %RH and capsule type on S, P, and D parameters. The moisture uptake of HG capsules were higher than HPMC capsules at all %RH conditions studied. It was found that values of D and P across HPMC capsules were greater than for HG capsules at 0-40 %RH; whereas over the same %RH range S values were higher for HG than for HPMC capsules. S values decreased gradually as the %RH was increased up to 60% RH. To probe the effect of moisture ingress, spray dried lactose was loaded into capsules. Phase evolution was characterised by scanning electron microscopy (SEM), X-ray powder diffraction (XRD), and differential scanning calorimetry (DSC). The capsules under investigation are not capable of protecting spray dried lactose from induced solid state changes as a result of moisture uptake. For somewhat less moisture sensitive formulations, HPMC would appear to be a better choice than HG in terms of protection of moisture induced deterioration.

An Acoustic-Based Method to Detect and Quantify the Effect of Exhalation into a Dry Powder Inhaler.

BACKGROUND: Dry powder inhaler (DPI) users frequently exhale into their inhaler mouthpiece before the inhalation step. This error in technique compromises the integrity of the drug and results in poor bronchodilation. This study investigated the effect of four exhalation factors (exhalation flow rate, distance from mouth to inhaler, exhalation duration, and relative air humidity) on dry powder dose delivery. Given that acoustic energy can be related to the factors associated with exhalation sounds, we then aimed to develop a method of identifying and quantifying this critical inhaler technique error using acoustic based methods. METHODS: An in vitro test rig was developed to simulate this critical error. The effect of the four factors on subsequent drug delivery were investigated using multivariate regression models. In a further study we then used an acoustic monitoring device to unobtrusively record the sounds 22 asthmatic patients made whilst using a Diskus(™) DPI. Acoustic energy was employed to automatically detect and analyze exhalation events in the audio files. RESULTS: All exhalation factors had a statistically significant effect on drug delivery (p<0.05); distance from the inhaler mouthpiece had the largest effect size. Humid air exhalations were found to reduce the fine particle fraction (FPF) compared to dry air. In a dataset of 110 audio files from 22 asthmatic patients, the acoustic method detected exhalations with an accuracy of 89.1%. We were able to classify exhalations occurring 5 cm or less in the direction of the inhaler mouthpiece or recording device with a sensitivity of 72.2% and specificity of 85.7%. CONCLUSIONS: Exhaling into a DPI has a significant detrimental effect. Acoustic based methods can be employed to objectively detect and analyze exhalations during inhaler use, thus providing a method of remotely monitoring inhaler technique and providing personalized inhaler technique feedback.

Predicting the physical state of spray dried composites: salbutamol sulphate/lactose and salbutamol sulphate/polyethylene glycol co-spray dried systems.

The effect of spray drying salbutamol sulphate, salbutamol sulphate/lactose and salbutamol sulphate/polyethylene glycol (PEG) solutions was investigated. Co-spray drying salbutamol sulphate with lactose, which is amorphous when spray dried alone, resulted in amorphous composites. Co-spray drying salbutamol sulphate with PEG 4000 and PEG 20,000, which do not form amorphous systems when spray dried alone, resulted in systems of varying crystallinity, the crystallinity depending on the weight ratio of polymer to drug. Examination of the physical properties of these salbutamol sulphate co-spray dried systems and those of bendroflumethiazide/PEG and lactose/PEG composites suggested that the formation and physical stability of amorphous composites prepared by spray drying is dependent on whether the glass transition temperature, Tg, of one of the two components is high enough to result in a Tg of the composite sufficiently high that the Kauzmann temperature of the mix is greater than the temperature of storage. The modified Gordon-Taylor equation proved to be useful in predicting the likelihood that a two-component composite will be amorphous on spray drying. Furthermore, the Gordon-Taylor equation was also useful in predicting the likely physical stability of amorphous two component composites and predicted that even polymers with apparently low Tgs, such as PEGs, may be stabilised in an amorphous composite by a suitable additive having a sufficiently high Tg.

The effect of spray drying solutions of bendroflumethiazide/polyethylene glycol on the physicochemical properties of the resultant materials.

The physicochemical properties of co-spray dried bendroflumethiazide (BFMT)/polyethylene glycol (PEG) 4000 composites were investigated. The co-spray dried composites produced from all BFMT/polymer solutions were amorphous. BFMT/PEG 4000 10 and 20% systems consisted of smooth spherical particles approximately 0.5-4mm in diameter. Spray drying resulted in no significant production of the main BFMT degradant, 5-trifluoromethyl-2,4-disulphamoylaniline (TFSA), and for composites consisting of 90% PEG 4000 by weight of total solids, spray drying appeared a superior method of production than the melt method which resulted in significant BFMT degradation. All BFMT/PEG compressed discs showed initial increased release of BFMT compared to discs of micronised BFMT alone, with the spray dried BFMT/PEG 4000 10% system showing initial rates two to three times that of BFMT alone. The physical stability of amorphous BFMT was reduced on inclusion of PEG 4000, recrystallisation occurring more quickly with increasing amount of PEG 4000 in the composites. PEG in the co-spray dried systems appeared to degrade on storage and recrystallised samples failed to show the presence of PEG by differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) or GPC. DSC results were consistent with BFMT/PEG forming a eutectic combination rather than a monotectic system.

The effect of spray drying solutions of polyethylene glycol (PEG) and lactose/PEG on their physicochemical properties.

The effect of spray drying polyethylene glycol (PEG) 4000 and lactose/PEG solutions was investigated. Micro-spherical PEG particles were successfully prepared from ethanol, which allowed lower outlet temperatures than water. The product was crystalline and consisted of rough spheres or rod like particles. In the case of lactose/PEG composites, spray dried from water, the crystallinity of both components was reduced on spray drying, the extent being dependent on the starting composition. Spray dried lactose/PEG with PEG present as 10% by weight was found to be the most amorphous of the systems prepared. Conversion to more crystalline products occurred over time, the rates of conversion being dependent on temperature and humidity. On storage at low humidity (31-34%) amorphous lactose in lactose/PEG spray dried systems converts to anhydrous crystalline lactose while at high humidity (75% RH) the monohydrate is formed. The rate of transformation of amorphous lactose to the crystalline monohydrate form, at high relative humidity, was quantified using the Avrami equation applied both to X-ray diffraction (XRD) peak intensity and heat of fusion data. Crystallisation of lactose appeared to be retarded at low PEG concentrations, where PEG was present predominantly in a non-crystalline state, but was accelerated at higher PEG contents.