Analysis of 3D Prints by X-ray Computed Microtomography and Terahertz Pulsed Imaging

Purpose

A 3D printer was used to realise compartmental dosage forms containing multiple active pharmaceutical ingredient (API) formulations. This work demonstrates the microstructural characterisation of 3D printed solid dosage forms using X-ray computed microtomography (XμCT) and terahertz pulsed imaging (TPI).

Methods

Printing was performed with either polyvinyl alcohol (PVA) or polylactic acid (PLA). The structures were examined by XμCT and TPI. Liquid self-nanoemulsifying drug delivery system (SNEDDS) formulations containing saquinavir and halofantrine were incorporated into the 3D printed compartmentalised structures and in vitro drug release determined.

Results

A clear difference in terms of pore structure between PVA and PLA prints was observed by extracting the porosity (5.5% for PVA and 0.2% for PLA prints), pore length and pore volume from the XμCT data. The print resolution and accuracy was characterised by XμCT and TPI on the basis of the computer-aided design (CAD) models of the dosage form (compartmentalised PVA structures were 7.5?±?0.75% larger than designed; n?=?3).

Conclusions

The 3D printer can reproduce specific structures very accurately, whereas the 3D prints can deviate from the designed model. The microstructural information extracted by XμCT and TPI will assist to gain a better understanding about the performance of 3D printed dosage forms.

     

Lyophilized Nanosuspensions for Oral Bioavailability Improvement of Insoluble Drugs: Preparation,Characterization, and Pharmacokinetic Studies

Purpose

We describe here a novel lyophilized nanosuspension technology in order to improve the dissolution rate and oral bioavailability of the insoluble drug P2X7 receptor antagonist (PRA), which is an effective antagonist to P2X7 receptor for non-steroidal anti-inflammatory.

Methods

PRA-lyophilized nanosuspension (PRA-LNS) was fabricated by anti-solvent precipitation in combination with high pressure homogenization, and then lyophilized for prolonged storage. After preparations, various characterization experiments were performed including particle size, zeta potential, surface morphology, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), in vitro dissolution study, and in vivo pharmacokinetic study.

Results

The re-dissolved particle size of PRA-LNS was about 180~250 nm with uniform distribution, confirmed by TEM image. The drug PRA in nanosuspensions possessed crystalline form evaluated via XRPD and DSC analysis. The solubility of PRA-LNS in water was 1.52 times larger than PRA raw drug; in vitro dissolution tests showed that PRA-LNS could dissolve completely within 5 min, which is a significant improvement compared to the raw drug. The relative bioavailability of PRA-LNS is 290.70% compared to the raw drug and 177.94% compared to the physical mixture.

Conclusions

PRA-LNS could easily re-disperse in water with increased solubility, enhanced oral bioavailability, and controllable production process.

     

Characterization of Self-Emulsifying Drug Delivery Systems Using In Situ Raman Spectroscopy to Study the Precipitation Inhibition Mechanism of Poorly Water-Soluble Drugs

Purpose

The goal of this research was to study the molecular interactions in situ between actives and surfactants in self-emulsifying delivery systems (SEDDS) in order to illuminate the factor(s) and how they influence the drug performance in these systems.

Method

We have developed an approach to evaluate the mechanism of performance of SEDDS formulations using an in situ Raman technique. Self-emulsifying delivery systems for seven actives with different physicochemical properties were formulated. One gram of the SEDDS was dispersed in 100 mL of media, and the precipitation behavior of the actives was noted. Using an immersion probe, these dispersions were tested continuously and spectra were obtained to determine the drug-excipient interactions.

Results

The changes in the molecular vibrational peaks confirmed that the drug-TPGS hydrogen bonding was responsible for maintaining the drug in solution. The interaction between Labrasol and the actives was weak and broke upon dispersion leading to precipitation of the drug. Also, the hydrogen bond donor strength of the functional group gave a good indication of the bond strength between TPGS and the drugs which determined the performance of the actives in the system.

Conclusion

It could be suggested that the hydrogen bond strength correlates well to the precipitation behavior from the SEDDS dispersions. Thus, studying the structures and physicochemical properties of the drug candidates and the excipients could significantly minimize the steps involved in developing successful lipid-based delivery systems.

     

Combined Used of Rheology and LF-NMR for the Characterization of PVP-Alginates Gels Containing Liposomes

Purpose

This paper is based on the characterization of the rheological and Low Field NMR (LF-NMR) properties of an interpenetrated hydrogel made up by poly(N-vinyl-2-pyrrolidone) and sodium alginate. The final aim is to use the hydrogel as a delivery matrix for liposomes, widely used tools in the drug delivery field.

Methods

Rheology, LF-NMR, TEM, cryo-TEM, confocal laser scanning microscopy and release test were employed to characterize the interpenetrated hydrogel. Different theoretical approaches such as Flory, Chui, Scherer and Schurz theories were used to interpret the experimental results.

Results

We found that the crosslinking mechanisms of the two polymers produced an anti-synergistic effect on the final mechanical properties of the interpenetrated hydrogel. Instead of creating a continuous network, alginate formed isolated, cross-linked, clusters embedded in a continuous network of poly(N-vinyl-2-pyrrolidone). Additionally, gel structure significantly influenced liposome delivery.

Conclusions

The rheological and LF-NMR characterization were confirmed and supported by the independent techniques TEM, cryo-TEM and release tests Thus, our findings reiterate the potentiality of both rheology and LF-NMR for the characterisation of soft materials such as interpenetrated polymeric networks.

     

Preparation of Drug-Loaded PLGA-PEG Nanoparticles by Membrane-Assisted Nanoprecipitation

Purpose

The aim of this work is to develop a scalable continuous system suitable for the formulation of polymeric nanoparticles using membrane-assisted nanoprecipitation. One of the hurdles to overcome in the use of nanostructured materials as drug delivery vectors is their availability at industrial scale. Innovation in process technology is required to translate laboratory production into mass production while preserving their desired nanoscale characteristics.

Methods

Membrane-assisted nanoprecipitation has been used for the production of Poly[(D,L lactide-co-glycolide)-co-poly ethylene glycol] diblock) (PLGA-PEG) nanoparticles using a pulsed back-and-forward flow arrangement. Tubular Shirasu porous glass membranes (SPG) with pore diameters of 1 and 0.2 μm were used to control the mixing process during the nanoprecipitation reaction.

Results

The size of the resulting PLGA-PEG nanoparticles could be readily tuned in the range from 250 to 400 nm with high homogeneity (PDI lower than 0.2) by controlling the dispersed phase volume/continuous phase volume ratio. Dexamethasone was successfully encapsulated in a continuous process, achieving an encapsulation efficiency and drug loading efficiency of 50% and 5%, respectively. The dexamethasone was released from the nanoparticles following Fickian kinetics.

Conclusions

The method allowed to produce polymeric nanoparticles for drug delivery with a high productivity, reproducibility and easy scalability.

     

Solid-State NMR Investigation of Drug-Excipient Interactions and Phase Behavior in Indomethacin-Eudragit E Amorphous Solid Dispersions

Purpose

To investigate the nature of drug-excipient interactions between indomethacin (IMC) and methacrylate copolymer Eudragit® E (EE) in the amorphous state, and evaluate the effects on formulation and stability of these amorphous systems.

Methods

Amorphous solid dispersions containing IMC and EE were spray dried with drug loadings from 20% to 90%. PXRD was used to confirm the amorphous nature of the dispersions, and DSC was used to measure glass transition temperatures (T_g). ¹³C and ¹⁵N solid-state NMR was utilized to investigate changes in local structure and protonation state, while ¹H T₁ and T_1ρ relaxation measurements were used to probe miscibility and phase behavior of the dispersions.

Results

T_g values for IMC-EE solid dispersions showed significant positive deviations from predicted values in the drug loading range of 40–90%, indicating a relatively strong drug-excipient interaction. ¹⁵N solid-state NMR exhibited a change in protonation state of the EE basic amine, with two distinct populations for the EE amine at ?360.7 ppm (unprotonated) and ?344.4 ppm (protonated). Additionally, ¹H relaxation measurements showed phase separation at high drug load, indicating an amorphous ionic complex and free IMC-rich phase. PXRD data showed all ASDs up to 90% drug load remained physically stable after 2 years.

Conclusions

¹⁵N solid-state NMR experiments show a change in protonation state of EE, indicating that an ionic complex indeed forms between IMC and EE in amorphous solid dispersions. Phase behavior was determined to exhibit nanoscale phase separation at high drug load between the amorphous ionic complex and excess free IMC.

     

Determination of Depth-Dependent Intradermal Immunogenicity of Adjuvanted Inactivated Polio Vaccine Delivered by Microinjections via Hollow Microneedles

Purpose

The aim of this study was to investigate the depth-dependent intradermal immunogenicity of inactivated polio vaccine (IPV) delivered by depth-controlled microinjections via hollow microneedles (HMN) and to investigate antibody response enhancing effects of IPV immunization adjuvanted with CpG oligodeoxynucleotide 1826 (CpG) or cholera toxin (CT).

Methods

A novel applicator for HMN was designed to permit depth- and volume-controlled microinjections. The applicator was used to immunize rats intradermally with monovalent IPV serotype 1 (IPV1) at injection depths ranging from 50 to 550 μm, or at 400 μm for CpG and CT adjuvanted immunization, which were compared to intramuscular immunization.

Results

The applicator allowed accurate microinjections into rat skin at predetermined injection depths (50–900 μm), -volumes (1–100 μL) and -rates (up to 60 μL/min) with minimal volume loss (±1–2%). HMN-mediated intradermal immunization resulted in similar IgG and virus-neutralizing antibody titers as conventional intramuscular immunization. No differences in IgG titers were observed as function of injection depth, however IgG titers were significantly increased in the CpG and CT adjuvanted groups (7-fold).

Conclusion

Intradermal immunogenicity of IPV1 was not affected by injection depth. CpG and CT were potent adjuvants for both intradermal and intramuscular immunization, allowing effective vaccination upon a minimally-invasive single intradermal microinjection by HMN.

     

Preparation,Physicochemical Characterization and Anti-fungal Evaluation of Nystatin-Loaded PLGA-Glucosamine Nanoparticles

Purpose

Nystatin loaded PLGA and PLGA-Glucosamine nanoparticles were formulated. PLGA were functionalized with Glucosamine (PLGA-GlcN) to enhance the adhesion of nanoparticles to Candida Albicans (C.albicans) cell walls.

Method

Quasi-emulsion solvent diffusion method was employed using PLGA and PLGA-GlcN with various drug–polymer ratios for the preparation of nanoparticles. The nanoparticles were evaluated for size, zeta potential, polydispersity index, drug crystallinity, loading efficiency and release properties. DSC, SEM, XRPD, ¹H-NMR, and FT-IR were performed to analyze the physicochemical properties of the nanoparticles. Antifungal activity of the nanoparticles was evaluated by determination of MICs against C.albicans.

Results

The spectra of ¹H-NMR and FT-IR analysis ensured GlcN functionalization on PLGA nanoparticles. SEM characterization confirmed that particles were in the nanosize range and the particle size for PLGA and PLGA-GlcN nanoparticles were in the range of 108.63?±?4.5 to 168.8?±?5.65 nm and 208.76?±?16.85 nm, respectively. DSC and XRPD analysis ensured reduction of the drug crystallinity in the nanoparticles. PLGA-GlcN nanoparticles exhibit higher antifungal activity than PLGA nanoparticles.

Conclusion

PLGA-GlcN nanoparticles showed more antifungal activity with appropriate physicochemical properties than pure Nystatin and PLGA nanoparticles.

     

Submicron Protein Particle Characterization using Resistive Pulse Sensing and Conventional Light Scattering Based Approaches

Purpose

Characterizing submicron protein particles (approximately 0.1–1μm) is challenging due to a limited number of suitable instruments capable of monitoring a relatively large continuum of particle size and concentration. In this work, we report for the first time the characterization of submicron protein particles using the high size resolution technique of resistive pulse sensing (RPS).

Methods

Resistive pulse sensing, dynamic light scattering and size-exclusion chromatography with in-line multi-angle light scattering (SEC-MALS) are performed on protein and placebo formulations, polystyrene size standards, placebo formulations spiked with silicone oil, and protein formulations stressed via freeze-thaw cycling, thermal incubation, and acid treatment.

Results

A method is developed for monitoring submicron protein particles using RPS. The suitable particle concentration range for RPS is found to be approximately 4?×?10⁷-1?×?10¹¹ particles/mL using polystyrene size standards. Particle size distributions by RPS are consistent with hydrodynamic diameter distributions from batch DLS and to radius of gyration profiles from SEC-MALS. RPS particle size distributions provide an estimate of particle counts and better size resolution compared to light scattering.

Conclusion

RPS is applicable for characterizing submicron particles in protein formulations with a high degree of size polydispersity. Data on submicron particle distributions provide insights into particles formation under different stresses encountered during biologics drug development.

     

Synthesis and Characterization of Nanocomposite Microparticles (nCmP) for the Treatment of Cystic Fibrosis-Related Infections

Purpose

Pulmonary antibiotic delivery is recommended as maintenance therapy for cystic fibrosis (CF) patients who experience chronic infections. However, abnormally thick and sticky mucus present in the respiratory tract of CF patients impairs mucus penetration and limits the efficacy of inhaled antibiotics. To overcome the obstacles of pulmonary antibiotic delivery, we have developed nanocomposite microparticles (nCmP) for the inhalation application of antibiotics in the form of dry powder aerosols.

Methods

Azithromycin-loaded and rapamycin-loaded polymeric nanoparticles (NP) were prepared via nanoprecipitation and nCmP were prepared by spray drying and the physicochemical characteristics were evaluated.

Results

The nanoparticles were 200 nm in diameter both before loading into and after redispersion from nCmP. The NP exhibited smooth, spherical morphology and the nCmP were corrugated spheres about 1 μm in diameter. Both drugs were successfully encapsulated into the NP and were released in a sustained manner. The NP were successfully loaded into nCmP with favorable encapsulation efficacy. All materials were stable at manufacturing and storage conditions and nCmP were in an amorphous state after spray drying. nCmP demonstrated desirable aerosol dispersion characteristics, allowing them to deposit into the deep lung regions for effective drug delivery.

Conclusions

The described nCmP have the potential to overcome mucus-limited pulmonary delivery of antibiotics.

     

Multifractal Characterization of Pharmaceutical Hot-Melt Extrudates

Purpose

Multifractal geometry has become a powerful tool to describe complex structures in many fields. Our first aim was to combine imaging and multifractal analysis to better understand the microstructure of pharmaceutical extrudates. A second objective was to study erosion/dispersion behavior of the formulations because it would condition release of any drug.

Methods

Different formulations containing a lipid, a polymer and different silica based inorganic carriers were produced by hot-melt extrusion at various screw speeds. Multifractal analysis was based on scanning electron microscopy/energy dispersive X-Ray spectroscopy images. This microstructural analysis was complemented with dynamic optical imaging of formulation erosion/dispersion behavior.

Results

Multifractal analysis indicated that inorganic carrier type and concentration as well as the screw speed affected the microstructure of the extrudates. The aqueous erosion/dispersion study showed that only the type and concentration of inorganic carrier were important.

Conclusions

The use of microstructural and dispersion analysis appeared to be complementary to better characterize and understand complex formulations obtained by hot-melt extrusion.

     

New Perspectives for Fixed Dose Combinations of Poorly Water-Soluble Compounds: a Case Study with Ezetimibe and Lovastatin

Purpose

Aiming to improve the dissolution rate of ezetimibe (EZE) and lovastatin (LOV) in a fixed dose combination (FDC), co-amorphous systems and ternary solid dispersions were prepared by quench cooling and spray drying, respectively.

Methods

Formulations were characterized through X-ray diffraction, modulated differential scanning calorimetry, infrared spectroscopy, scanning electron microscopy and laser diffraction, and evaluated by ‘in vitro’ dissolution. Stability studies were conducted at different conditions during 30 days with the ternary solid dispersion composed of 75% of Soluplus® (ELS 1:1 75%).

Results

Single phase co-amorphous systems made up of the pure drugs were not able to increase the dissolution rate of EZE and LOV. However, ternary solid dispersions achieved high dissolution for both compounds, especially when Soluplus® was used as carrier. The dissolution efficiency increased up to 18 (EZE) and 6 (LOV) times in ternary solid dispersions, compared to the crystalline drugs. ELS 1:1 75% preserved its amorphous state during 30 days, in different stability conditions.

Conclusions

A spray dried ternary solid dispersion able to enhance the dissolution rate of two poorly soluble, therapeutically complementary drugs, is reported for the first time. These promising results open new perspectives for the development of more advanced FDCs.

     

Supramolecular Cocrystals of Gliclazide: Synthesis,Characterization and Evaluation

Purpose

To prepare the supramolecular cocrystals of gliclazide (GL, a BCS class II drug molecule) via mechanochemical route, with the goal of improving physicochemical and biopharmaceutical properties.

Methods

Two cocrystals of GL with GRAS status coformers, sebacic acid (GL-SB; 1:1) and α-hydroxyacetic acid (GL-HA; 1:1) were screened out using liquid assisted grinding. The prepared cocrystals were characterized using thermal and analytical techniques followed by evaluation of antidiabetic activity and pharmacokinetic parameters.

Results

The generation of new, single and pure crystal forms was characterized by DSC and PXRD. The crystal structure determination from PXRD revealed the existence of both cocrystals in triclinic (P-1) crystal system. The hydrogen bonded network, determined by material studio was well supported by shifts in FTIR and SSNMR. Both the new solid forms displayed improved solubility, IDR, antidiabetic activity and pharmacokinetic parameters as compared to GL.

Conclusions

The improvement in these physicochemical and biopharmaceutical properties corroborated the fact that the supramolecular cocrystallization may be useful in the development of pharmaceutical crystalline materials with interesting network and properties.

     

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.

     

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.

     

Morphometric Characterization of Rat and Human Alveolar Macrophage Cell Models and their Response to Amiodarone using High Content Image Analysis

Purpose

Progress to the clinic may be delayed or prevented when vacuolated or “foamy” alveolar macrophages are observed during non-clinical inhalation toxicology assessment. The first step in developing methods to study this response in vitro is to characterize macrophage cell lines and their response to drug exposures.

Methods

Human (U937) and rat (NR8383) cell lines and primary rat alveolar macrophages obtained by bronchoalveolar lavage were characterized using high content fluorescence imaging analysis quantification of cell viability, morphometry, and phospholipid and neutral lipid accumulation.

Results

Cell health, morphology and lipid content were comparable (p < 0.05) for both cell lines and the primary macrophages in terms of vacuole number, size and lipid content. Responses to amiodarone, a known inducer of phospholipidosis, required analysis of shifts in cell population profiles (the proportion of cells with elevated vacuolation or lipid content) rather than average population data which was insensitive to the changes observed.

Conclusions

A high content image analysis assay was developed and used to provide detailed morphological characterization of rat and human alveolar-like macrophages and their response to a phospholipidosis-inducing agent. This provides a basis for development of assays to predict or understand macrophage vacuolation following inhaled drug exposure.

     

Real-Time UV Imaging of Nicotine Release from Transdermal Patch

Purpose

This study was conducted to characterize UV imaging as a platform for performing in vitro release studies using Nicorette® nicotine patches as a model drug delivery system.

Methods

The rate of nicotine release from 2 mm diameter patch samples (Nicorette®) into 0.067 M phosphate buffer, pH 7.40, was studied by UV imaging (Actipix SDI300 dissolution imaging system) at 254 nm. The release rates were compared to those obtained using the paddle-over-disk method.

Results

Calibration curves were successfully established which allowed temporally and spatially resolved quantification of nicotine. Release profiles obtained from UV imaging were in qualitative agreement with results from the paddle-over-disk release method.

Conclusion

Visualization as well as quantification of nicotine concentration gradients was achieved by UV imaging in real time. UV imaging has the potential to become an important technology platform for conducting in vitro drug release studies.

     

Rheological Characterization of Molten Polymer-Drug Dispersions as a Predictive Tool for Pharmaceutical Hot-Melt Extrusion Processability

Purpose

The aim of this study was to investigate (i) the influence of drug solid-state (crystalline or dissolved in the polymer matrix) on the melt viscosity and (ii) the influence of the drug concentration, temperature and shear rate on polymer crystallization using rheological tests.

Methods

Poly (ethylene oxide) (PEO) (100.000 g/mol) and physical mixtures (PM) containing 10–20–30–40% (w/w) ketoprofen or 10% (w/w) theophylline in PEO were rheologically characterized. Rheological tests were performed (frequency and temperature sweeps in oscillatory shear as well as shear-induced crystallization experiments) to obtain a thorough understanding of the flow behaviour and crystallization of PEO-drug dispersions.

Results

Theophylline did not dissolve in PEO as the complex viscosity (η*) of the drug-polymer mixture increased as compared to that of neat PEO. In contrast, ketoprofen dissolved in PEO and acted as a plasticizer, decreasing η*. Acting as a nucleating agent, theophylline induced the crystallization of PEO upon cooling from the melt. On the other hand, ketoprofen inhibited crystallization upon cooling. Moreover, higher concentrations of ketoprofen in the drug-polymer mixture increasingly inhibited polymer crystallization. However, shear-induced crystallization was observed for all tested mixtures containing ketoprofen.

Conclusion

The obtained rheological results are relevant for understanding and predicting HME processability (e.g., barrel temperature selection) and downstream processing such as injection moulding (e.g., mold temperature selection).

     

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.

     

The Impact of Solid Dispersion on Formulation,Using Confocal Micro Raman Spectroscopy as Tool to Probe Distribution of Components

Purpose

Solid dispersions (SDs) of a poorly water-soluble drug were prepared, and their physicochemical properties were compared to those of control physical mixtures (PMs). Among the multiple techniques used to characterize the solid state of preparations, confocal micro Raman spectroscopy (CMRS) was used as a non-destructive tool to qualitatively probe content uniformity and distribution of drug and carrier.

Methods

SDs and PMs of drug (fenbendazole, FBZ) were prepared containing two different carriers (poloxamer P188 or P407) with different drug polymer ratios. The preparations were characterized by powder X-ray diffractometry, Fourier transform infrared spectroscopy, thermal analysis, scanning electron microscopy, and in vitro dissolution assay. In addition, CMRS technique and principal component analysis (PCA) were used in order to statistically define the content uniformity and distribution of the drug within the polymeric matrix.

Results

In vitro dissolution results exhibited a marked improvement when the drug was formulated as SD compared to control PM and to pure drug. The solid state of these preparations characterized by X-ray powder diffraction and Fourier transform infrared spectroscopy showed no changes in the crystalline state of the drug and no chemical interactions between the components. Raman studies showed a better content uniformity of the drug within the polymeric matrix when subjected to SD process, correlating with the improved dissolution profile.

Conclusion

This study provides evidence of the potential of the confocal Raman imaging technique, providing a fast and powerful method to characterize solid dispersions which could be incorporated towards the use of quality by design (QbD) approaches in pharmaceutical development.