An investigation of nifedipine miscibility in solid dispersions using Raman spectroscopy.

PURPOSE: Raman spectroscopy is potentially an extremely useful tool for the understanding of drug-polymer interactions in solid dispersions. This is examined and demonstrated for the case of solid dispersions of nifedipine in a polymeric substrate. METHODS: Solid dispersions consisting of nifedipine and polyvinyl caprolactam--polyvinyl acetate--polyethylene glycol graft copolymer (Soluplus®) were prepared by freeze drying, melting and solvent evaporation at drug loadings of 10, 30, 50, 70 and 90% w/w. Drug-polymer interactions in the amorphous solid dispersion were estimated by Raman spectroscopy. The correlation between the solid state stability of the drug in a solid dispersion and the extent of drug-polymer interaction was monitored by X-ray diffractometry. RESULTS: The miscibility limit of nifedipine-Soluplus® was found to be 30% w/w drug loading for all preparation methods. The drug was found to interact with Soluplus®, through a hydrophilic interaction identified by infrared spectroscopy and a hydrophobic interaction which could be quantified by Raman spectroscopy. The average extent of the drug-polymer interaction in the studied amorphous samples at equivalent drug loading was similar, regardless of the preparation method. Inhomogeneities in samples prepared by melting contributed to a wider variation in drug-polymer interaction and poorer solid state stability, in terms of its crystallization tendency. CONCLUSIONS: Raman spectroscopy was shown to be a useful technique in classifying miscibility levels based on the hydrophobic interaction between the drug and the polymer. Different drug loadings showed varying degrees of drug-polymer interaction, and hence variable solid state stability of the solid dispersion.

Synthesis of VIP-lipopeptide using a new linker to modify liposomes: towards the development of a drug delivery system for active targeting.

A new component for the solid phase peptide synthesis of lipopeptide, 2-[(4R,5R)-5-({[(9H-fluoren-9-yl)methoxy]carbonylaminomethyl}-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]acetic acid (2), was designed and synthesized from (-)-2,3-O-isopropylidene-D-threitol (3) in 4 steps. The key step was the selective alkylation of 3 with benzyl bromoacetate in the presence of Cs2CO3. Vasoactive intestinal peptide (VIP)-lipopeptide (1) incorporating this linker was synthesized by solid phase peptide synthesis.

High drug loading self-microemulsifying/micelle formulation: design by high-throughput formulation screening system and in vivo evaluation.

PURPOSE: To design a high drug loading formulation of self-microemulsifying/micelle system. METHODS: A poorly-soluble model drug (CH5137291), 8 hydrophilic surfactants (HS), 10 lipophilic surfactants (LS), 5 oils, and PEG400 were used. A high loading formulation was designed by a following stepwise approach using a high-throughput formulation screening (HTFS) system: (1) an oil/solvent was selected by solubility of the drug; (2) a suitable HS for highly loading was selected by the screenings of emulsion/micelle size and phase stability in binary systems (HS, oil/solvent) with increasing loading levels; (3) a LS that formed a broad SMEDDS/micelle area on a phase diagram containing the HS and oil/solvent was selected by the same screenings; (4) an optimized formulation was selected by evaluating the loading capacity of the crystalline drug. Aqueous solubility behavior and oral absorption (Beagle dog) of the optimized formulation were compared with conventional formulations (jet-milled, PEG400). RESULTS: As an optimized formulation, d-α-tocopheryl polyoxyethylene 1000 succinic ester: PEG400 = 8:2 was selected, and achieved the target loading level (200 mg/mL). The formulation formed fine emulsion/micelle (49.1 nm), and generated and maintained a supersaturated state at a higher level compared with the conventional formulations. In the oral absorption test, the area under the plasma concentration-time curve of the optimized formulation was 16.5-fold higher than that of the jet-milled formulation. CONCLUSIONS: The high loading formulation designed by the stepwise approach using the HTFS system improved the oral absorption of the poorly-soluble model drug.

Quantification of pharmaceutical polymorphs and prediction of dissolution rate using theophylline tablet by terahertz spectroscopy.

Theophylline has an anhydrous form and a monohydrated form, and the dissolution rate of the anhydrous form is higher than that of the monohydrated form. Terahertz (THz) spectra of theophylline tablet containing the theophylline anhydrous form, monohydrated form, microcrystalline cellulose and magnesium stearate exhibited a specific absorption peak at 0.96 THz, where the theophylline anhydrous form demonstrated an absorption peak. Additionally, the intensity of the peak at 0.96 THz gradually decreased as the proportion of the anhydrous form decreased. The multivariate data analysis was performed to correlate the THz spectra of theophylline tablets with the ratio of the theophylline anhydrous form. The calibration model used to predict the mixing ratio of the theophylline anhydrous form from the THz spectra achieved root-mean-squared errors of cross-validation (RMSECV) of 2.89%, a slope of 0.9934 and an R(2) of 0.9927. In addition, there were intentions to develop a prediction model for the dissolution rate of theophylline from the drug product. The dissolution rate of theophylline tablet was gradually delayed as the proportion of the anhydrous form was decreased. The multivariate data analysis was performed to correlate the THz spectra of theophylline tablets with the dissolution rate. The calibration model used to predict the percentage of theophylline dissolved in 45 min from the THz spectra achieved an RMSECV of 3.29%, a slope of 0.9260 and an R(2) of 0.9423. Furthermore, there were no significant differences between the predicted and measured percentages of theophylline dissolved in 45 min in the theophylline tablets that were stored at 84% relative humidity (RH) and 25 °C for 12 h or 3 d.

Effect of physical properties of troglitazone crystal on the molecular interaction with PVP during heating.

This study examined the effect of physical properties of troglitazone drug substance on the molecular interaction with polyvinylpyrrolidone K30 (PVP) during preparation by a closed melting method. Milling was conducted using impact and jet mills to change the physical properties of troglitazone, such as particle size, specific surface area, surface free energy and acidic-basic parameters. Solid dispersions (SDs) prepared from milled troglitazone, irrespective of milling method, showed almost 100% dissolution when not less than 7.5% of water was added during heating. SDs prepared from unmilled troglitazone showed almost 100% dissolution when not less than 12.8% of water was added during heating. Physical mixture (PM) containing unmilled troglitazone must be heated above at least 50 degrees C higher than the glass transition temperature (T(g)) of PVP to obtain an SD showing 100% dissolution, while PMs containing milled troglitazone could be heated above only 20 degrees C higher than the T(g) of PVP to obtain an SD showing 100% dissolution. The melting points of troglitazone in PMs containing milled troglitazone, irrespective of milling method, were lower than those in PMs containing unmilled troglitazone. These results indicated that specific interaction could occur more easily during heating between milled troglitazone and PVP during preparation by a closed melting method. In addition, Fourier transform infrared study indicated that hydrogen bonding could occur between the N-H of troglitazone and the C=O of PVP.

Application of Eudragit RS to thermo-sensitive drug delivery systems: II. Effect of temperature on drug permeability through membrane consisting of Eudragit RS/PEG 400 blend polymers.

The Eudragit RS and polyethylene glycol 400 (PEG 400) blend polymer (EPG) membranes were prepared by the solvent casting method to pioneer a novel application of Eudragit RS to a thermo-sensitive material. The EPG membranes containing 2.5-10% PEG 400 (2.5-10% EPG) showed the glass transition temperatures (Tgs) around the body temperature (32-42 degrees C). Drug permeation studies through the EPG membranes were carried out using acetaminophen (AAP) and aminopyrine (AMP) as the model drugs. The permeability of AAP and AMP through the EPG membranes has been shown to be a discontinuous function of temperature, that is, their permeability increased steeply above the Tg of the membranes. The amount of AMP permeated at 42 degrees C was nearly eight times as much as that at 36 degrees C. Arrhenius plots of the steady-state permeability coefficient (P) of AAP indicated two straight lines that intersect at the Tg of the 10% EPG membrane. In the water uptake study for the 10% EPG membrane, the degree of the swelling for the membrane tended to increase with increasing temperature above the Tg of the membrane. The thermo-sensitive permeation mechanism for the EPG membranes might be based on the structure change of the membranes caused by the glass transition, so that the membranes could absorb more water. Considering the high biological safety of Eudragit RS and PEG 400, the EPG membranes might be used to develop a novel thermo-sensitive drug delivery system.

Effects of sugar ester and hydroxypropyl methylcellulose on the physicochemical stability of amorphous cefditoren pivoxil in aqueous suspension.

The improvement in physicochemical stability of amorphous cefditoren pivoxil (CDTR-PI) in aqueous suspensions by addition of sugar ester (SE) and hydroxypropyl methylcellulose (HPMC) was explained by prolonging the induction period prior to crystallization and the reduction in crystal peak intensity. Furthermore, the stabilizing effect of these additives in a multiple additive system was greater than in a single additive system. To determine the mechanism, by which these additives stabilized the amorphous CDTR-PI, we evaluated the surface states of CDTR-PI in suspension by measuring Raman spectra and zeta potential. The change in Raman spectra demonstrated that SE and HPMC interacted with CDTR-PI at the same interaction sites on CDTR-PI. The zeta potential reflected the adsorption phenomena of the additives and indicated that both SE and HPMC adsorbed onto particles of CDTR-PI with no apparent competitive interaction and the response was complementary. It was considered, based on this study, that HPMC and SE would stabilize amorphous CDTR-PI by different mechanisms; HPMC would mainly inhibit crystal growth by small amount of adsorption and SE would inhibit both crystal growth and nucleation by large amount of adsorption. This was considered to result in the hybrid effect in the multiple additive system.

Dissolution mechanism of poorly water-soluble drug from extended release solid dispersion system with ethylcellulose and hydroxypropylmethylcellulose.

The purpose of this study is to investigate the release mechanism of poorly water-soluble drug from the extended release solid dispersion systems with water-insoluble ethylcellulose (EC) and water-soluble hydroxypropylmethylcellulose (HPMC) (1:1). Indomethacin (IND) was used as a model of poorly water-soluble drug. Two kinds of solid dispersions were prepared by the solvent evaporation methods, which consist of the same formulation but exhibit different physical performance. It appeared that the dissolution behavior of IND depended on the structures of EC-HPMC matrices, which were governed by the preparation method. In addition, the dissolution behavior showed pH dependency that the dissolution rate of IND was slower in acidic medium than that in neutral medium. The experimental results revealed that the hydrophobic interaction between IND and EC occurred under lower pH and strongly delayed the dissolution rate of IND. The relationship between this hydrophobic interaction and the dissolution rate of IND was also proposed.

Effects of water content in physical mixture and heating temperature on crystallinity of troglitazone-PVP K30 solid dispersions prepared by closed melting method.

Troglitazone, which possesses two asymmetric carbons, is obtained as a mixture of four isomers present in equal amounts. Troglitazone (Lot T003) has two melting points, about 120 and 175 degrees C. To increase the bioavailability of insoluble troglitazone, troglitazone-polyvinylpyrrolidone K30 (PVP) solid dispersions (SDs) were prepared with water by a unique closed melting method. In this study, the effects of the water content in the physical mixture (PM) and the heating temperature on the apparent crystallinity of troglitazone in SDs prepared by this method were investigated. When the water content in the PM was controlled at 3%, although the apparent crystallinity of troglitazone in the SD prepared by heating at 105 degrees C did not decrease (99%), that of the SDs prepared by heating at 130 and 150 degrees C were reduced to 54 and 11%, respectively. This result indicated that the meltage of troglitazone varies depending on the heating temperature. The apparent crystallinity of troglitazone in the SDs decreased with increase in water content in the PM. In particular, SDs prepared by heating at 130 and 150 degrees C showed 0% apparent crystallinity when the water content in the PM were more than 13 and 8%, respectively. When the heating temperature used was higher than the glass transition temperature of PVP plasticized with water, troglitazone crystals were dissolved in the rubbery PVP. Therefore, even if the heating temperature is lower than the melting point of troglitazone during preparation, controlling the water content in the PM at a high level can produce a troglitazone SD with 0% apparent crystallinity.

Possibility of monitoring granulation by analyzing the amount of hydroxypropylcellulose, a binder on the surface of granules, using ToF-SIMS.

The purpose of this study was to clarify the mechanism responsible for high-shear wet granulation using time-of-flight secondary ion mass spectrometry (ToF-SIMS), which can be used for surface chemical mapping. A total of 15 kinds of granules, including hydroxypropylcellulose (HPC) as a binder, were obtained in a model formulation using different granulation conditions, such as the amount of sprayed water and the granulation time. Surface chemical mapping of these granules was then performed using a ToF-SIMS analysis, which distinguishes each component by detecting the specific mass-to-charge ratio (m/z). As a result, we found that HPC got to appear on the surface of granule with proceeding wet granulation. By considering this result, we concluded that the distributions of HPC might be closely related to the progress of granule consolidation and growth in wet granulation. Therefore, the progress of granulation can likely be understood by measuring the content of HPC on the granule surface.

Changes in surface properties by granulation and physicochemical stability of granulated amorphous cefditoren pivoxil with additives.

The evaluation of the physicochemical stability of granules of amorphous cefditoren pivoxil (CDTR-PI), alone or with polymers, demonstrated that granulated amorphous CDTR-PI with hydroxypropyl methylcellulose was the most stable. We measured glass transition temperature by differential scanning calorimetry (DSC). The molecular mobility of the whole granules did not change, and it was not consistent with the results of the evaluation of physicochemical stability. Peak shifts were observed in IR spectra of amorphous CDTR-PI with polymers after granulation, and the shifts were similar to those observed for spray-dried samples. Furthermore, the shifts were not observed after the granules were ground. Acid-base parameters, which were also measured by inverse gas chromatography (IGC), changed after granulation. These results suggested that on the surface of the granules, CDTR-PI and the polymers would be mixed monomolecularly, as in the spray-dried samples. The changes in the molecular state of a drug when mixed monomolecularly with a polymer on the surface of granules were successfully confirmed by IGC and IR.

Prediction of passive intestinal absorption using bio-mimetic artificial membrane permeation assay and the paracellular pathway model.

The purpose of this study was to construct and examine the prediction model for total passive permeation through the intestinal membrane. The paracellular pathway prediction model based on Renkin function (PP-RF) was combined with a bio-mimetic artificial membrane permeation assay (BAMPA), which is an in vitro method to predict transcellular pathway permeation, to construct the prediction model (BAMPA-PP-RF model). The parameters of the BAMPA-PP-RF model, e.g. apparent pore radius and potential drop of the paracellular pathway, were calculated from BAMPA permeability, the dissociation constant, the molecular radius and the fraction of a dose absorbed in humans consisting of 80 structurally diverse compounds. The apparent pore radius and the apparent potential drop obtained in this study were 5.61-5.65 A and 75-86 mV, respectively, and these were in accordance with the previously reported values. The mean square root error of the BAMPA-PP-RF model was 13-14%. The BAMPA-PP-RF model was shown to be able to predict the total passive permeability more adequately than BAMPA alone.

Clarifying the mechanism of aggregation of particles in high-shear granulation based on their surface properties by using micro-spectroscopy.

The present study aimed to clarify, by means of micro-spectroscopy, the mechanism of aggregation of particles into granules during high-shear granulation. We used two types of pharmaceutical granules prepared by high-shear granulator, one containing mefenamic acid and the other containing flavoxate hydrochloride as poorly soluble active pharmaceutical ingredients (APIs). Lactose, cornstarch, and microcrystalline cellulose were used as excipients; and hydroxypropyl cellulose (HPC) was used as the binding agent. The distributions of components in granules were visualized by mapping cross-sections of individual granules with techniques utilizing mid-infrared spectroscopy at the SPring-8 synchrotron radiation facility and micro-Raman spectroscopy. In the distribution maps of mefenamic acid granules, distributions of mefenamic acid, cornstarch, and microcrystalline cellulose overlapped; in flavoxate hydrochloride granules, on the other hand, distributions of flavoxate hydrochloride and lactose overlapped. Assessment of the surface free energy of each component found that ingredients with overlapping distribution had similar surface properties. Therefore, it was revealed that in high-shear granulation, in addition to the granulator operating conditions and general properties of the formulation itself (such as the solubility and particle size of each ingredient), the surface properties of the ingredients and their interrelationships were also factors that determined the aggregation behavior of the particles.

Low-density microparticles with petaloid surface structure for pulmonary drug delivery.

The morphology of spray-dried particles composed of psicose and hydroxypropyl methylcellulose was modified by adding ammonium bicarbonate (ABC) to the solution. The surface structure of the particles was altered by immediate transformation of ABC to gaseous components during the spray drying. As a result, low-density microparticles with a petaloid surface structure, which was controllable by changing the evaporation rate of ABC, was obtained. This technique should be useful for modifying characteristics of solid particles for pulmonary drug delivery.

[Liposome modified with VIP-lipopeptide as a new drug delivery system].

We have designed a novel lipid analog (lipopeptide) that mimics the structural features of modified phospholipids. This lipopeptide is easily synthesized using a peptide synthesizer and has been shown to be useful for the modification of liposomes, which are used as an active targeted drug delivery system (DDS). Vasoactive intestinal peptide (VIP) has high homology with pituitary adenylate cyclase activating peptide (PACAP). There are three major PACAP receptors: PAC1R, VPAC1R, and VPAC2R. PAC1R has affinity only for PACAP, whereas VPAC1R and VPAC2R have the same affinity for both VIP and PACAP. In the present study, we synthesized several lipopeptides conjugated with VIP through different linkers and found that liposomes modified with these lipopeptides (VIP-Lips) selectively recognized the PACAP/VIP receptors. The anti-cancer activity of these VIP-Lips was evaluated by encapsulation of an antitumor drug, doxorubicin (DOX), into the modified liposomes (VIP-Lips-DOX) against the human osteosarcoma cell line, Saos-2, which highly expresses the VIP receptor. cAMP production was then measured to determine how well the VIP-Lips were able to recognize VPAC2R. The results clearly indicate that the proposed lipopeptide methodology holds promise as a DDS for cancer therapy.

Quantitative analysis of the layer separation risk in bilayer tablets using terahertz pulsed imaging.

Layer separation is a critical defect in many bilayer tablets. Despite its importance for product quality, few studies have investigated its root cause. We evaluated bilayer tablets with varying layer separation tendencies using terahertz pulsed imaging (TPI) in comparison with other analytical methods such as tensile strength measurements, friability testing, scanning electron microscopy (SEM), and X-ray computed tomography (XRCT). The layer separation risk was determined by friability testing and shown to be correlated with the final compression pressure used for bilayer tablet fabrication. TPI could nondestructively detect cracks between the component layers that lead to layer separation. The adhesion integrity of the interface was quantified by the interface index, a unique value derived from the time-domain terahertz waveform. The interface index showed good correlation to the layer separation tendency and could distinguish interface quality among seven batches of bilayer tablets. In contrast, SEM and XRCT detected structural defects but could not distinguish batches with high or low layer separation risk. TPI revealed the relationship between compression pressure and interface quality. Thus, TPI can aid in quality control by providing a precise estimate of the layer separation risk and robust quality of bilayer tablet development with better understanding of layer separation.

Advanced technologies for assessment of polymer swelling and erosion behaviors in pharmaceutical aspect.

Clearly understanding of swelling kinetics and erosion behavior of polymer can reveal drug release mechanism and kinetics. Recently, swelling progression and mobility of water molecule inside polymers have been investigated by several technologies, including magnetic resonance imaging (MRI), X-ray microtomography (XµT), Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), fluorescent, texture analyzer, and ultrasound techniques. Each technique offers its own advantages which suit to different study purposes. This review describes application of the advanced technologies to monitor swelling-erosion behaviors and also compares pros and cons of each technique. This may help the researchers to select the appropriate technique for their polymer.

Importance of excipient wettability on tablet characteristics prepared by moisture activated dry granulation (MADG).

For moisture activated dry granulation (MADG), microcrystalline cellulose (MCC) or silicon dioxide is recommended for the moisture absorption stage. The aim of this study was to assess the suitability of alternative excipients as moisture absorbents with regard to the disintegration mechanism of resulting lactose based placebo formulations. Beside high and low moisture MCC grades, the additions of magnesium aluminometasilicate (MAMS), pregelatinized starch (S1500), crospovidone (Kollidon CL) and carmellose calcium (ECG 505) were evaluated. High shear granulation (HSG) was conducted as a reference process. The overall disintegration time of all tablets produced by MADG was significantly faster whereas hardness yield and mass-variability were equal or superior compared to the HSG process. Powder wettability of the different moisture absorbents was identified to be a key driver for rapid disintegration, whereas tablet porosity had only a minor influence on the target hardness of the tablets.

Application of multiple stepwise spinning disk processing for the synthesis of poly(methyl acrylates) coated chitosan-diclofenac sodium nanoparticles for colonic drug delivery.

The production of pharmaceutical nanoparticles by the spinning disk processing (SDP) technique has advantages in terms of its scalability and its capacity to produce readily tunable nanoparticles of narrow size distribution. In this study, we successfully developed a novel multiple stepwise SDP technique to develop aggregates of uniformly sized poly(methyl acrylates)-coated chitosan-diclofenac sodium nanocores (CS-PMA NPs) for colonic drug delivery. The processing conditions were optimized using the Box-Behnken design. SEM and TEM micrographs showed the optimized system to consist of 10 µm-sized agglomerates of CS-PMA NPs, the latter measuring 10nm in diameter. High drug entrapment of 88% was attained. Potential colon-targeted drug release from the CS-PMA NPs was demonstrated, with retardation of drug release in simulated gastrointestinal fluids and over 90% of the drug load released into simulated colonic fluid within 8 h. Drug uptake from CS-PMA NPs into Caco-2 cells was threefold higher than that from a control drug solution, with no apparent cytotoxicity observed at the NP doses administered. The collective data suggest that the SDP is a robust manufacturing method that can potentially be used to scale up the production of composite nanoparticulate colon-targeted drug delivery systems.

Cocrystallization and amorphization induced by drug-excipient interaction improves the physical properties of acyclovir.

Although acyclovir is one of the most important antiviral drugs used today, there are several problems with its physical properties. The aim of this study is to prepare cocrystals or amorphous complex of acyclovir using drug-excipient interactions to improve the physical properties of the drug, especially its dissolution rate and transdermal absorption. Screening for formation of cocrystals and the presence of amorphous acyclovir was conducted with various pharmaceutical excipinents, with the use of the solution-crystallization method and liquid-assisted cogrinding. The potential cocrystalline phase and the amorphized complex were characterized by PXRD, TG/DTA, IR, DSC and HPLC techniques. The screening indicated that acyclovir formed novel cocrystals with tartaric acid and was amorphized with citric acid. The acyclovir-tartaric acid cocrystal (ACV-TA cocrystal) structure was determined from synchrotron X-ray powder diffraction data. T(g) of the amorphous acyclovir-citric acid compound (ACV-CA amorphous) was determined by DSC. The initial dissolution rate of the ACV-TA cocrystals was considerably faster than that of anhydrous acyclovir. In vitro skin permeation of ACV-CA amorphous from polyethylene glycol (PEG) ointment was remarkably higher than that of the crystalline acyclovir. We successfully improved the physical properties of acyclovir by the cocrystallization and amorphization techniques, using pharmaceutical excipients.