Co-ground Products Research Articles

Product contamination during mechanochemical synthesis of praziquantel co-crystal, polymeric dispersion and cyclodextrin complex

This paper aims to evaluate the product contamination by elemental impurities during the mechanochemical synthesis of praziquantel (PZQ) co-crystal, polymeric dispersion and cyclodextrin complex by grinding. To assess that, PZQ was co-ground with malic acid (MA), Poloxamer F-127 (F-127) and hydroxypropyl-β-cyclodextrin (HPβCD) in high-energy vibrational mills using stainless steel and agate grinding tools, applying different processing time (30 and 90 min). Differential scanning calorimetry and X-ray powder diffraction confirmed the formation of the targeted products, regardless of applied processing time and grinding tool type. After digestion of the solid powder products, the levels of selected elemental impurities were analysed by inductively coupled plasma mass spectrometry (ICP-MS). The analysis revealed that the content of Mg, Ca, and V are below the limit of quantification in all samples analysed. The contents of P and Na are not related to the type of ball mill and reaction time, but to the starting materials themselves, considering that Na is found in HPβCD and MA, while P was found in F-127. The detected Si impurities in the co-ground products can be related to the use of the agate balls and jars, while the presence of Cr and Fe can be related to the use of the stainless steel grinding tools. The risk assessment showed that the oral administration of the prepared co-ground products in quantities corresponding to regular PZQ oral doses resulted in only insignificant exposure to Cr. Finally, the use of agate grinding tools should be preferred, as administration of such products results in lower Cr exposure. The presented elemental impurities did not lead to any significant drug degradation as PZQ content at the end of the six-month testing period was still in the range of 95–105 % of the initial content. Regardless, ICP-MS analysis of the elemental impurities should be considered in regular quality control procedures in the development and production of novel pharmaceutical products prepared by grinding.

Optimization of mechanically assisted coamorphous dispersion extraction of hydrophobic compounds from plant tea (Citri Reticulatae Pericarpium) using water

This study aimed to establish a novel mechanically assisted coamorphous dispersion extraction (MADE) method for the extraction of hydrophobic compounds (hesperidin, nobiletin and tangeretin) from Citri Reticulatae Pericarpium using water. The surface morphology, particle size distributions, phase states and functional groups of the coground product surface were characterized by Scanning Electron Microscopy, X-ray diffraction and Fourier transform infrared spectroscopy. The parameters affecting the efficiency of extraction method were optimized by single-factor experiments and response surface methodology. The method showed good linear relationships in the range of 1–500 μg/mL with correlation coefficients (R2) ≥ 0.9990, low limits of detection ranging from 3.0 to 28.3 ng/mL, and acceptable recoveries ranging from 87.0 to 91.0%. Therefore, the proposed MADE method is a promising, efficient and organic solvent-free method for the extraction of hydrophobic compounds from plant tea.

Development of Solvent-Free Co-Ground Method to Produce Terbinafine Hydrochloride Cyclodextrin Binary Systems; Structural and In Vitro Characterizations.

Molecular complexation with cyclodextrins (CDs) has long been a known process for modifying the physicochemical properties of problematic active pharmaceutical ingredients with poor water solubility. In current times, the focus has been on the solvent-free co-grinding process, which is an industrially feasible process qualifying as a green technology. In this study, terbinafine hydrochloride (TER), a low solubility antifungal drug was used as a model drug. This study aimed to prepare co-ground products and follow through the preparation process of the co-grinding method in the case of TER and two amorphous CD derivatives: (2-hydroxypropyl)-β-cyclodextrin (HPBCD); heptakis-(2,6-di-O-methyl)-β-cyclodextrin (DIMEB). For this evaluation, the following analytical tools and methods were used: phase solubility studies, differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), hot-stage X-ray powder diffractometry (HOT-XRPD), Fourier-transform infrared (FT-IR), Raman spectroscopy, and Scanning Electron Microscopy (SEM). Furthermore, in vitro characterization (dissolution and diffusion studies) was performed in two kinds of dissolution medium without enzymes. In the XRPD and SEM studies, it was found that the co-grinding of the components resulted in amorphous products. FT-IR and Raman spectroscopies confirmed the formation of an inclusion complex through the unsaturated aliphatic chain of TER and CDs. In vitro characterization suggested better dissolution properties for both CDs and decreased diffusion at higher pH levels in the case of HPBCD.

Co-grinding with surfactants as a new approach to enhance in vitro dissolution of praziquantel

This paper evaluates the process of co-grinding with a surfactant as a new approach to enhance physicochemical and biopharmaceutical properties of praziquantel (PZQ), a poorly soluble drug that is essential for the treatment of schistosomiasis, a neglected tropical disease. Surfactants used in this study were poloxamer F-127 and sucrose stearate (C-1816), selected based on their well-documented biocompatibility and solubilizing activity. A series of products were prepared by mechanochemical activation using vibrational ball-mill at different drug to surfactant ratio and milling times. The obtained products were characterised in terms of drug recovery, solubility and in vitro dissolution rates. The obtained results were correlated to solid-state properties of the products analysed by differential scanning calorimetry, powder X-ray diffraction and particle size analysis. Results of UPLC-MS analysis and 1H-NMR spectroscopy showed that the used surfactants and applied grinding procedures caused no chemical degradation of the PZQ. The physicochemical properties, solubility and the in vitro dissolution enhancement of the co-ground products were related to the drug to surfactant ratio and the grinding protocol applied. The highest enhancement of the in vitro dissolution rate was achieved at the drug to surfactant ratio of 10:3 and 10:2 for F-127 and C-1816, respectively with the milling time of 30 min. The MTT assay on Caco-2 cell line demonstrated the biocompatibility of both co-ground products. Furthermore, the surfactants used did not change intrinsically high intestinal permeability of PZQ (Papp ∼ 4.00 × 10−5 cm s−1). The presented results confirmed that the co-grinding with surfactant is a promising new approach in enhancing in vitro dissolution of poorly soluble drugs like PZQ.

Combined Approach of Cyclodextrin Complexationand Nanostructured Lipid Carriers for the Development of a Pediatric Liquid Oral Dosage Form of Hydrochlorothiazide.

The development of specific and age-appropriate pediatric formulations is essential to assure that all children and their care-givers can easily access to safe and effective dosage forms. The need for developing specific pediatric medicinal products has been highlighted by the European Medicines Agency. The aim of this study was to investigate the effectiveness of combining the advantages of both cyclodextrin (CD) complexation and loading into nanostructured lipid carriers (NLC), to obtain a liquid oral pediatric formulation of hydrochlorothiazide (HCT), endowed with safety, dosage accuracy, good stability and therapeutic efficacy. Equimolar drug combinations as physical mixture (P.M.) or coground product (GR) with hydroxypropyl-β-cyclodextrin (HPβCD) or sulfobutylether-β-cyclodextrin (SBEβCD) were loaded into NLC, then characterized for particle size, homogeneity, Zeta potential, entrapment efficiency, gastric and storage stability. The presence of HPβCD allowed higher entrapment efficacy than NLC loaded with the plain drug, and enabled, in the case of GR systems a complete and sustained drug release, attributable to the wetting and solubilising properties of HPβCD toward HCT. In vivo studies on rats proved the superior therapeutic effectiveness of HCT-in HPβCD-in NLC formulations compared to the corresponding free HCT-loaded NLC, thus confirming the successfulness of the proposed approach in the development of an efficacious liquid oral formulation of the drug.

Development and in vivo evaluation of an innovative “Hydrochlorothiazide-in Cyclodextrins-in Solid Lipid Nanoparticles” formulation with sustained release and enhanced oral bioavailability for potential hypertension treatment in pediatrics

An innovative pediatric oral formulation of hydrochlorothiazide (HCT) (2mg/mL), endowed with improved bioavailability and sustained release properties and suitable for the hypertension treatment in pediatric patients, was developed by combining the drug-cyclodextrin complexation and the incorporation of the complex into Solid Lipid Nanoparticles (SLN). Precirol®ATO5-based SLN, with two different surfactants (Pluronic®F68 and Tween®80) loaded with the drug as such or as binary system with hydroxypropyl-beta-cyclodextrin (HPβCd) and sulfobutyl-ether-beta-cyclodextrin (SBEβCd) both as physical mixture (P.M.) or coground product (GR), were prepared using the hot high-shear homogenization followed by ultrasonication method. Loading of the drug:HPβCd both as P.M. and GR gave rise to nanoparticle formation, differently from the HCT:SBEβCd ones, with an entrapment efficiency of about 65%. Such SLN formulations showed an improvement of the drug release rate compared both to the drug suspension and to the free drug-loaded SLN. In all cases the SLN containing the GR systems exhibited better performances than the corresponding with P.M. However, the presence of Tween®80 gave rise to the complete drug release after only 150min, without providing a sustained release, whereas Pluronic®F68-based SLN containing GR were able to assure a sustained release over the time achieving more than 75% drug released at the end of the test, maintaining a constant 1.8-fold increase respect to simple drug suspension. Pluronic®F68-based SLN showed a pharmaceutically acceptable stability up to three months. In vivo studies highlighted the effectiveness of such formulations, enabling a concomitant increased diuretic effect and a sustained drug release and, consequently, enhanced HCT oral bioavailability.

Analysis of physicochemical properties of ternary systems of oxaprozin with randomly methylated-ß-cyclodextrin and l-arginine aimed to improve the drug solubility

The influence of l-arginine on the complexing and solubilizing power of randomly-methylated-β-cyclodextrin (RameβCD) towards oxaprozin, a very poorly soluble anti-inflammatory drug, was examined. The interactions between the components were investigated both in solution, by phase-solubility analysis, and in the solid state, by differential scanning calorimetry, FTIR and X-ray powder diffractometry. The morphology of the solid products was examined by Scanning Electron Microscopy. Results of phase-solubility studies indicated that addition of arginine enhanced the RameβCD complexing and solubilizing power of about 3.0 and 4.5 times, respectively, in comparison with the binary complex (both at pH≈6.8). The effect of arginine was not simply additive, but synergistic, being the ternary system solubility higher than the sum of those of the respective drug-CD and drug-arginine binary systems. Solid equimolar ternary systems were prepared by physical mixing, co-grinding, coevaporation and kneading techniques, to explore the effect of the preparation method on the physicochemical properties of the final products. The ternary co-ground product exhibited a dramatic increase in both drug dissolution efficiency and percent dissolved at 60min, whose values (83.6 and 97.1, respectively) were about 3 times higher than the sum of those given by the respective drug-CD and drug-aminoacid binary systems. Therefore, the ternary co-ground system with arginine and RameβCD appears as a very valuable product for the development of new more effective delivery systems of oxaprozin, with improved safety and bioavailability.

Comparative analysis of binary and ternary cyclodextrin complexes with econazole nitrate in solution and in solid state

The aim of this work was to investigate in-depth interactions of econazole nitrate (ECN), a very poorly water-soluble antifungal agent, with different β-cyclodextrin (βCD) derivatives, and to evaluate the potential synergistic effect of suitable third compounds (l-amino acids, citric acid, hydrophilic polymers). Phase-solubility studies showed the formation of equimolar complexes with all tested CDs, and indicated sulfobutyl-βCD (SBEβCD) as the best complexing and solubilizing agent for ECN, followed by hydroxypropyl-βCD (HPβCD). 1D and 2D 1H NMR studies demonstrated the actual formation of inclusion complexes of 1:1mol:mol stoichiometry, and gave insight about different inclusion modes of ECN molecule into the CD cavity, simultaneously existing in solution. Among the different tested ternary systems, only those with citric acid (CA) enabled a significant increase in complexing and solubilizing ability towards the drug with respect to the binary ones, indicating a synergistic effect between SBEβCD and CA and the formation of highly soluble ternary complexes, which was further supported by NMR studies. Solid equimolar binary and ternary systems of ECN, CDs and CA were prepared by co-grinding in high energy vibrational micro-mills and characterized by differential scanning calorimetry, X-ray powder diffractometry and in vitro dissolution studies. In the case of binary systems, total sample amorphization, indicative of strong solid state interactions and possible inclusion complex formation, was obtained only for co-ground products with HPβCD and SBEβCD, but they both presented a dissolution profile typical of a supersaturated system, with a limited improvement of drug dissolution efficiency (8.3 and 22.13 times, respectively). On the contrary, the ternary ECN/SBEβCD/CA co-ground product presented superior dissolution properties, increasing the ECN dissolution efficiency of 66.62 times, clearly having the best potential for further development of a novel ECN delivery system for efficient delivery of the drug to the oral cavity, thus improving the therapy of oral candidosis.

Physico-chemical characterization in solution and in the solid state of clonazepam complexes with native and chemically-modified cyclodextrins

Clonazepam (CLZ) is a benzodiazepine derivative, whose bioavailability, limited by its very poor water-solubility, could be improved by cyclodextrin complexation. However, the choice of the most proper cyclodextrin to use to fully exploit its potential favourable effects on the drug, is a critical step. Therefore, in the present work, the performance of some amorphous cyclodextrin (CD) derivatives in terms of complexing, solubilizing and amorphizing power towards CLZ was carefully evaluated and compared with that of natural CDs. The role of CD cavity size, amorphous or crystalline nature, and presence and type of substituents on its ability in producing effective interactions with the drug has been investigated. Equimolar CLZ–CD solid systems were obtained by blending, kneading, co-grinding and coevaporation. Drug–CD interactions were investigated by phase-solubility analysis, differential scanning calorimetry and X-ray powder diffractometry. Among the natural CDs, β-CD showed the highest complexing ability, suggesting that its cavity size is the most proper to host the drug molecule. The presence of substituents had a negative effect on the performance of α-CD and γ-CD, while it improved the complexing and solubilizing power of β-CD, and the methylated derivative was more effective than the hydroxypropylated one. Solid-state studies revealed that amorphous CDs had highest amorphizing power than the corresponding natural crystalline ones, and methylated-β-CD (Me-β-CD) was the best carrier. As for the preparation method, co-grinding was the most powerful in promoting the formation of efficacious drug–CD solid-state interactions. Dissolution rate studies confirmed Me-β-CD as the best partner for CLZ and co-grinding as the best method for maximizing the drug dissolution properties. Therefore, co-ground products with Me-β-CD could be selected as the best system for future development of CLZ formulations with improved therapeutic efficacy.

Processing and formulation of drug nanoparticles by ternary cogrinding with methacrylic copolymer and sucrose fatty acid esters

Drug nanoparticles were prepared by cogrinding three components: a drug, a methacrylic copolymer, and sucrose fatty acid ester (SE). A high nanoparticle yield was obtained when cholesterol-lowering probucol (PBC), a poorly water–soluble drug, was used in the cogrinding process with D-1811, an SE with stearic acid as the fatty acid and the hydrophile–lipophile balance (HLB): 11. Investigation of the influence of HLB on SEs constituted with stearates revealed that the nanoparticle yield increased with increasing HLB of the SE; a particle-size distribution of about 100nm (thought to originate from the drug) was observed. The PBC crystallinity was analyzed by powder X-ray diffraction and Raman spectroscopy before and after grinding. Its crystalline form changed from form I to form II with partial generation of the amorphous state. Granules with improved drug solubility and controlled-release performance were prepared by coating the particles with an aqueous suspension of the coground product. Observation of the coated granule surfaces by SEM and polarization microscopy revealed about a 10-μm-thick coating layer. In a dissolution test, controlled drug-release characteristics were observed under intestinal solubility conditions. Based on these results, functional pharmaceutical granules with enteric and sustained drug release were prepared.

Zaleplon co-ground complexes with natural and polymeric β-cyclodextrin

In this study, we compared the suitability of parent β-cyclodextrin (βCD) and its water soluble polymeric derivative (PβCD) as co-grinding additives aimed to enhance the solubility of zaleplon (ZAL), a hypnotic drug. Equimolar drug/carrier mixtures were co-ground in a high-energy micromill over different time intervals. Data obtained by differential scanning calorimetry, X-ray powder diffractometry and scanning electron microscopy showed a higher affinity of ZAL for the solid state interaction with PβCD, resulting in powders with lower relative drug crystallinity (RDC) compared to that obtained with natural βCD (RDC = 51.10 and 12.5 % for complexes with βCD and PβCD co-grounded for 90 min, respectively). On the other hand, grinding the drug alone did not result in a significant reduction of the drug crystallinity (RDC = 99.87 % for the sample ground for 90 min). Although 1H-NMR spectroscopy confirmed that both co-ground products were readily converted into inclusion complexes upon dissolution in water, they presented different dissolution properties. The dissolution velocity of co-ground complex with PβCD was 25 % faster compared to that prepared with the parent βCD and almost double compared to that of the drug alone, irrespective of the pH value of the dissolution media. This clearly demonstrated the suitability of co-ground ZAL/PβCD complex in the development of an immediate release oral formulation of ZAL.

Improvement of oxaprozin solubility and permeability by the combined use of cyclodextrin, chitosan, and bile components

The effect of the combined use of randomly methylated β-cyclodextrin (RAMEB), chitosan (CS), and bile components (dehydrocholic (DHCA) or ursodeoxycholic (UDCA) acids and their sodium salts) on solubility and permeability through Caco-2 cells of oxaprozin (a very poorly water-soluble non-steroidal anti-inflammatory drug) has been investigated. Addition of CS, bile acids, and their sodium salts increased the RAMEB solubilizing power of 4, 2, and 5 times, respectively. Drug–RAMEB–CS co-ground systems showed very higher dissolution rate than corresponding drug–RAMEB systems. Addition of bile components further improved drug dissolution rate. The CS presence enabled a significant increase in drug permeability through Caco-2 cells with respect to drug–RAMEB systems. Moreover, CS and NaDHC showed a synergistic enhancer effect, enabling a 1.4-fold permeability increase in comparison with systems without bile salt. However, unexpectedly, no significant differences were found between physical mixtures and co-ground products, indicating that drug permeation improvement was due to the intrinsic enhancer effect of the carriers and not to drug-carrier interactions brought about by co-grinding, as instead found in dissolution rate studies. The combined use of RAMEB, CS, and NaDHC could be exploited to develop effective oral dosage forms of oxaprozin, with increased drug solubility and permeability, and then improved bioavailability.

Solid state mechanochemical simultaneous activation of the constituents of the Silybum marianum phytocomplex with crosslinked polymers

Simultaneous improvement of solubilization kinetics of main flavolignans of Silybum marianum extract was obtained cogrinding with two crosslinked polymers: micronized crospovidone, PVP-CL® and sodium carboxymethylcellulose, Ac-Di-Sol® in the 1:3 active-to-polymer weight ratio. By this process it was assessed that the main extract components lost its crystalline structure, and the powder surface area was increased by 2.1- and 1.7-fold in the coground products with Ac-Di-Sol® and PVP-CL®, respectively. This activated status of the dry extract remained stable over a period of 2 years. Solubilization kinetics resulted ameliorated both in terms of entire dry extract and in terms of single components. When the 1/3 coground systems with PVP-CL® and Ac-Di-Sol® were dissolved in saturated conditions they gave a concentration improvement compared to the native product of 8 and 31 times of silybin A, 7 and 27 times of silybin B, whereas in the case of silychristin a double concentration was obtained only using Ac-Di-Sol®. The in vivo studies on rats confirmed that this solubilization improvement corresponded to an effective oral bioavailability enhancement. The highest bioavailability improvement was obtained with Ac-Di-Sol®, with a relative bioavailability of 88.6, 17.96, and 16.4 compared to the extract for silybin A, silybine B, and silychristine, respectively.

Evaluation of supercritical fluid technology as preparative technique of benzocaine–cyclodextrin complexes—Comparison with conventional methods

The objective of this study was to investigate the effect of the preparation method on the physico-chemical properties of complexes prepared between β-cyclodextrin (β-Cyd) and benzocaine (BZC). In particular, the effectiveness of a new technique based on supercritical carbon dioxide (SC CO 2) for preparing solid drug–cyclodextrin complexes was investigated and compared to other more conventional methods such as kneading (KN), co-evaporation (COE), co-grinding (GR) and sealed-heating (S.H.). Effects of temperature, pressure and exposure time on the properties of complexes prepared by SC CO 2 technology were also studied. The different systems were characterized by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffractometry (PXRD) and dissolution test according to the dispersed amount method. The co-grinding (GR) method resulted in amorphous products while other methods led to crystalline or partially amorphous products depending on both the method and its experimental conditions. SC CO 2 method revealed to be an effective technique for preparing solid systems between β-cyclodextrin and benzocaine, avoiding the use of organic solvents (and problems of their complete removal) and allowing an easy scale-up of the process. As for the influence of the experimental conditions in promoting the solid-state drug–carrier interaction when using the SC CO 2 method, temperature seemed to play the major role, whereas pressure and exposure times had more limited effects. Dissolution tests confirmed a limited but favourable effect in increasing the exposure time, while indicated a possible interaction effect between temperature and pressure in influencing the dissolution performance of the final product. The best product obtained by the SC CO 2 method showed dissolution properties similar to those of the co-ground product and only slightly lower than the system obtained by sealed-heating, which was the most effective technique.

Interaction of naproxen with ionic cyclodextrins in aqueous solution and in the solid state

The possible role of the cyclodextrin charge in the interaction with an acidic drug such as naproxen (p K a 4.8) has been evaluated. Sulfobutylether-ß-cyclodextrin (SBE-ßCyd) and trimethylammonium-ß-cyclodextrin (TMA-ßCyd) were selected as, respectively, anionically and cationically charged carriers and their performance was compared with that of the parent ß-cyclodextrin (ßCyd) and of its methyl-derivative (MeßCyd) previously found as the best partner for the drug. Interactions in solution were investigated by phase-solubility, fluorescence and circular dichroism analyses. Equimolar drug–carrier products prepared by different techniques (blending, cogrinding, sealed-heating, colyophilization) were characterized by differential scanning calorimetry and X-ray powder diffractometry and tested for drug dissolution properties. Anionic charges of SBE-ßCyd did not negatively influence interactions in unbuffered aqueous solutions (pH ≈5) with the acidic drug. In fact, it was a very effective carrier, exhibiting solubilizing and complexing properties considerably better than the parent ßCyd and comparable to those of MeßCyd. On the contrary, the positive charges of TMA-ßCyd did not favour interactions with the counter-ionic drug (despite the presence of about 60% ionised drug) and it was less efficacious also than native ßCyd. Therefore, the role of the Cyd charge on the complexing and solubilizing properties towards naproxen was not important whereas other factors, such as steric hindrance effects and favourable hydrophobic interactions were significant in determining the drug affinity for the Cyd inclusion. Solid state studies evidenced similar amorphizing properties of both charged Cyds towards naproxen. On the other hand, dissolution tests, in agreement with solution studies, showed that all products with SBE-ßCyd exhibited significantly better dissolution properties than the corresponding ones with TMA-ßCyd. A clear influence of the preparation method of drug–Cyd solid systems on the performance of the end product was also observed. Colyophilization was the most effective technique, followed by the cogrinding one. Colyophilized product with SBE-ßCyd allowed a 10-times increase in drug dissolution efficiency (D.E.) (with respect to the five-times increase obtained with the corresponding coground product) and a reduction of t 50% from about 60 min (for the coground product) to less than 2 min.

Comparative Study on Co-Ground Products of Rofecoxib with -Cyclodextrin and Its Sulfobutyl Ether-7 Derivative in Solution and in the Solid State

The inclusion behavior of sulfobutyl ether-7 derivative ofβ-cyclodextrin (SBE7βCD), in solution and solidstate was compared with that of natural β-cyclodextrin(βCD) toward a poorly water-soluble anti-inflammatoryagent, rofecoxib (ROFX), chemically 4[4-(methylsulfonyl)phenyl]-3-phenyl-2 (5H)-furazone. Drug-cyclodextrin solidsystems were prepared by cogrinding in a ball mill. A phasesolubility method was used to evaluate the stoichiometries andstability constants of ROFX-βCD (1 : 1 and 62 M-1)and ROFX-SBE7βCD (1 : 1 and 132 M-1) complexes.The formation of inclusion complexes with βCD andSBE7βCD in the solid state were confirmed by infraredspectroscopy, differential scanning calorimetry, X-ray diffractometry,scanning electron microscopy and in the liquid state by phasesolubility analysis, nuclear magnetic resonance spectroscopy andcircular dichroism studies. Dissolution studies using the USP paddlemethod were carried out in phosphate buffer pH 7.2 at 37 °Cfor both βCD and SBE7βCD complexes of rofecoxib.Solubility enhancement was much greater for the rofecoxib-SBE7βCDcomplex compared to drug-βCD complex. The stability constantobtained for the SBE7βCD inclusion complex of rofecoxib wasthe highest. Finally, dissolution profiles obtained suggest thatSBE7βCD is more effective than β-cyclodextrin inimproving the pharmaceutical properties of rofecoxib.

Solid-state characterization and dissolution properties of Naproxen–Arginine–Hydroxypropyl-β-cyclodextrin ternary system

The effect of ternary complexation of naproxen, a poorly water soluble anti-inflammatory drug, with hydroxypropyl-β-cyclodextrin and the basic aminoacid L-arginine on the drug dissolution properties has been investigated. Equimolar binary (drug–cyclodextrin or drug–arginine) and ternary (drug–cyclodextrin–arginine) systems were prepared by blending, cogrinding, coevaporation, and characterized by differential scanning calorimetry, thermogravimetric analysis, FT-IR spectroscopy, X-ray diffractometry. The dissolution behavior of naproxen from the different products was evaluated by means of a continuous flow through method. The results of solid state studies indicated the presence of strong interactions between the components in ternary coevaporated and coground systems, which were both of totally amorphous nature. In contrast, the presence of either free drug or free arginine was detected when the third component (cyclodextrin or aminoacid) was physically mixed, respectively, to the drug–arginine binary system (as physical mixture, coevaporate, or coground product) or to the drug–cyclodextrin binary system (as physical mixture, coevaporate, or coground product). All ternary combinations were significantly ( P<0.001) more effective than the corresponding binary drug-cyclodextrin and drug–arginine systems in improving the naproxen dissolution rate. The best performance in this respect was given by the ternary coevaporate, with about 15 times increase in terms of both drug relative dissolution rate and dissolution efficiency. The synergistic effect of the simultaneous use of arginine and cyclodextrin on the dissolution rate of naproxen was attributed to the combined effects of inclusion in cyclodextrin and salt formation, as well as to a specific role played by arginine in this interaction.

Influence of chitosan and its glutamate and hydrochloride salts on naproxen dissolution rate and permeation across Caco-2 cells

Chitosan and its glutamate and hydrochloride salts were evaluated for their efficacy in improving the dissolution behaviour of naproxen (a poorly water-soluble antiinflammatory drug) and its transport in vitro across Caco-2 cell monolayers. Drug–polymer physical mixtures and coground products, prepared at two different w/w ratios (30/70 and 10/90), were characterized by differential scanning calorimetry, X-ray powder diffractometry, scanning electron microscopy, and tested for dissolution properties. Coground systems were more effective than physical mixtures in improving drug dissolution and chitosan base, in spite of its lower water solubility, showed higher solubilizing power than its salts. According to the solid state analyses results, this effect was directly related to its stronger amorphizing power. Transport studies showed that only coground mixtures with chitosan glutamate salt allowed a significant drug apparent permeability improvement; however, they did not exhibit appreciable effects on the Caco-2 tight junctions (measured by the trans-epithelial electrical resistance variations), thus indicating that their enhancer effect was mainly due to an improved naproxen transport by transcellular passive diffusion rather than through the paracellular route. The direct compression properties and antiulcerogenic activity together with the demonstrated dissolution and permeation enhancer abilities toward naproxen make chitosan glutamate an optimal carrier for developing fast-action oral solid dosage forms of this drug.

Solid-state characterization of glyburide-cyclodextrin co-ground products

Natural crystalline (α-, β-, γ-) and amorphous derivative (hydroxypropyl-β- and methyl-β) cyclodextrins were selected as potential carriers for obtaining, through a co-grinding technique, a stable activated amorphous form of glyburide with improved dissolution properties. Differential scanning calorimetry (DSC) was used to investigate solid-state modifications of the drug induced by co-grinding with the selected carriers in a high energy vibrational micro-mill. X-ray powder diffraction and FTIR spectroscopy were employed as additional techniques to support DSC data. Equimolar drug : cyclodextrin physical mixtures were co-ground for different times (up to 60 min) at constant vibration frequency (24 Hz). A progressive drug amorphization with increasing grinding time was observed in all binary systems, but, interestingly, different degrees of sensitivity to the mechanical-chemical activation were evident. In fact, blends with natural cyclodextrins, despite the initial higher crystallinity than those with the amorphous derivatives, required the same or shorter co-grinding times (60 min) to achieve complete drug amorphization. Stability studies indicated no appreciable drug recrystallization in co-ground products after 4 months storage in sealed containers at 25°C or 1 month at 25°C and 75% RH. No stability differences were detected between products with natural or derivative cyclodextrins. The results accounted for the suitability of cyclodextrin co-grinding technique to obtain and stabilize glyburide in the activated amorphous form.

Enhancement of Dehydroepiandrosterone Solubility and Bioavailability by Ternary Complexation with α‐Cyclodextrin and Glycine

In the present work we investigated the possibility of improving dehydroepiandrosterone (DHEA) solubility and bioavailability by high‐energy cogrinding with α‐cyclodextrin (α‐Cd) in the presence or absence of different auxiliary substances (glycine, biomaltodextrin, poly(vinyl pyrrolidone), poly(ethylene glycol) 400). In all cases, ternary products exhibited higher drug solubilizing properties than the binary DHEA–α‐Cd coground system. Glycine was the most effective component. The best combinations, corresponding to 1:1:2 and 1:2:3 drug–α‐Cd–glycine molar ratios, were characterized by differential scanning calorimetry and X‐ray powder diffractometry and evaluated for dissolution rate. The presence of glycine favored destruction of DHEA crystalline structure during cogrinding, as evidenced by the strong reduction in both time and vibration frequency of milling necessary to obtain total drug amorphization. Both ternary products showed better dissolution properties than the drug alone, affording, respectively, a 40 and 60% increase of dissolution efficiency. The 1:2:3 coground product was then selected for in vivo bioavailability studies in women suffering from adrenocortical insufficiency. DHEA and DHEA sulfate blood levels were significantly higher (p < 0.001) after oral administration of the coground product than after oral administration of untreated drug, with a 100% increase in the area under the curve (AUC) of concentration versus time. Moreover, the time to reach maximum concentration (tmax) decreased from 2.2 with the untreated drug to 0.5h with the coground product, and the mean permanence time of DHEA within physiological levels was four times longer for the coground product compared with the untreated drug. These results indicate that the developed product is particularly suitable for oral DHEA formulations in hormone replacement therapies. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2177–2184, 2003