Novel ultra-cryo milling and co-grinding technique in liquid nitrogen to produce dissolution-enhanced nanoparticles for poorly water-soluble drugs

A novel ultra-cryo milling micronization technique for pharmaceutical powders using liquid nitrogen (LN2 milling) was used to grind phenytoin, a poorly water-soluble drug, to improve its dissolution rate. LN2 milling produced particles that were much finer and more uniform in size and shape than particles produced by jet milling. However, the dissolution rate of LN2-milled phenytoin was the same as that of unground phenytoin due to agglomeration of the submicron particles. To overcome this, phenytoin was co-ground with polyvinylpyrrolidone (PVP). The dissolution rate of co-ground phenytoin was much higher than that of original phenytoin, single-ground phenytoin, a physical mixture of phenytoin and PVP, or jet-milled phenytoin. X-Ray diffraction showed that the crystalline state of mixtures co-ground by LN2 milling remained unchanged. The equivalent improvement in dissolution, whether phenytoin was co-ground or separately ground and then mixed with PVP, suggested that even when co-ground, the grinding of PVP and phenytoin occurs essentially independently. Mixing original PVP with ground phenytoin provided a slight improvement in dissolution, indicating that the particle size of PVP is important for improving dissolution. When mixed with ground phenytoin, PVP ground by LN2 milling aided the wettability and dispersion of phenytoin, enhancing utilization of the large surface area of ground phenytoin. Co-grinding phenytoin with other excipients such as Eudragit L100, hypromellose, hypromellose acetate-succinate, microcrystalline cellulose, hydroxypropylcellulose and carboxymethyl cellulose also improved the dissolution profile, indicating an ultra-cryo milling and co-grinding technique in liquid nitrogen has a broad applicability of the dissolution enhancement of phenytoin.     

Inclusion complex of 3,9-bis(N,N-dimethylcarbamoyloxy)-5H-benzofuro[3,2-c]quinoline-6-one (KCA-098) with heptakis(2,6-di-O-methyl)-beta-cyclodextrin: interaction and dissolution properties

Interactions of KCA-098 with heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD) in solution and in the solid state were studied by the solubility method, UV and fluorescence spectroscopy, powder X-ray diffractometry, and thermal analysis. The KCA-098/DM-beta-CyD system showed an A(L) type solubility diagram with stability constants of 5870 and 2220 M(-1) in aqueous and 10% methanol solutions, respectively. Following the addition of DM-beta-CyD, the maximum UV wavelength of KCA-098 was shifted to a longer wavelength and the fluorescence intensity was decreased. A similar spectral change was observed when KCA-098 was dissolved in less polar solvents, especially in proton-acceptor solvents, such as acetone and dimethylsulfoxide, suggesting that KCA-098 interacts with DM-beta-CyD through not only a hydrophobic interaction but also hydrogen bonding. The solid complex of KCA-098 with DM-beta-CyD in a molar ratio of 1:1 was prepared by the kneading method and the solvent evaporation method, using organic solvents. Powder X-ray diffractometric and differential scanning calorimetric studies indicated that KCA-098 was dispersed as microparticles on the DM-beta-CyD complex in the solid state prepared by the solvent evaporation method although it dispersed as crystals in the sample prepared by the kneading method. The dissolution of KCA-098 from the solid complex prepared by the former method was markedly faster than that prepared by the latter method, although it slowed down with the passage of time. The reduced dissolution of KCA-098 was explained by crystallization to the hydrate form in the medium. These data indicate that poorly water-soluble KCA-098 interacts with DM-beta-CyD in water and in the solid state and that a fast-dissolving form of KCA-098 can be obtained by evaporating with DM-beta-CyD using organic solvents.     

Studies of rapidly disintegrating tablets in the oral cavity using co-ground mixtures of mannitol with crospovidone

We attempted the development of rapid oral disintegration tablets by direct compression using co-ground mixture of D-mannitol and crospovidone. The co-ground mixture was prepared with a vibration rod mill. The tablets were formed by compression using a single punch-tableting machine after addition of the co-ground mixture to non-ground D-mannitol, crospovidone and magnesium stearate. Regarding the properties of tablets, hardness and the time of disintegration were measured. The particle diameter and specific surface area of the co-ground mixture were measured. The tablets manufactured from a physical mixture of 30% (w/w) co-ground mixture of D-mannitol and crospovidone (mixed ratio 9 :1) with 65.5% (w/w) of non-ground mannitol, 4% (w/w) of crospovidone, and 0.5% (w/w) of magnesium stearate had good properties for rapidly disintegrating tablets in the oral cavity. They showed the hardness of 4.9 kg and disintegration time of 33 s. We found that adding co-ground mixture of D-mannitol and crospovidone is useful in enhancing hardness of the tablets that could not be achieved by addition of their individually ground mixture. The improvement in the hardness of the tablets was also observed when other saccharides and disintegrants were used. This method was proved to be applicable in the manufacture of tables of ascorbic acid, a water-soluble drug and nifedipine, a slightly water soluble drug; and the dissolution rate of nifedipine from the tablets in water was remarkably improved. The particle sizes of D-mannitol in the co-ground mixture were smaller than that of the individually ground mixture, resulting in a larger specific surface area of the co-ground mixture than that of the individually ground mixture. Therefore, it was presumed that crospovidone acted as a grinding assistant for D-mannitol in the co-grinding process, enhancing the hardness of tablets by increasing the contact area among powder particles.     

Preformulation study of nicergoline solid dispersions

Nicergoline, a semisynthetic ergot derivative, which, in its crystalline state, is insoluble in water, was dispersed in polyvinylpyrrolidone K30 (PVP K30) to improve drug particle dissolution. Preformulation studies were carried out initially by differential scanning calorimetry and X-ray powder diffraction in order to predict the conditions and the possibility to actually obtain solid dispersions by mixing the two components at different proportions. Solid dispersions were finally prepared by dissolving nicergoline and PVP K30 in chloroform that was next evaporated under reduced pressure. Under these conditions, an amorphous powder was recovered in every proportion of the two components. Nicergoline demonstrated to be physically and chemically stable for 1 year. The dissolution studies revealed a very high dissolution rate of nicergoline from solid dispersions only lower than the pure amorphous form. This is the consequence of the molecular dispersion of nicergoline in the polymer that enhances the rate of drug release from the polymer.     

The effect of physical state on the drug dissolution rate

In this work, the enhancement of drug dissolution rate through the preparation of new formulations containing Nimodipine in molecular level dispersion or in nanodispersion into poly(vinyl pyrrolidone) (PVP) matrix, was investigated. Differential scanning calorimetry (DSC) and modulated-temperature differential scanning calorimetry (MTDSC) in combination with X-ray powder diffractometry (XRPD) and scanning electron microscopy (SEM) studies showed that Nimodipine was amorphous in solid dispersions of 10 or 20 mass%, and mainly dispersed on a molecular level. This behaviour is attributed to the strong interactions taking place between the amine group of Nimodipine and carbonyl group of PVP. At higher drug loadings, crystal reflections in XRPD patterns and melting peaks of Nimodipine in DSC traces, indicated presence of drug in crystalline form. Micro-Raman studies in combination with SEM micrographs showed that the mean particle size increases with drug content in the formulations, up to 10 μm. Moreover, both XRPD patterns and micro-Raman spectra seem to indicate that Nimodipine crystallized in a second, thermodynamically stable, crystal modification II. The physicochemical characteristics of Nimodipine and the particle size distribution directly affect the dissolution rate enhancement, which is higher in amorphous dispersions.     

Improvement of dissolution property of poorly water-soluble drug by novel dry coating method using planetary ball mill

The dissolution property of a poorly water-soluble drug, flurbiprofen (FP), was improved by a novel dry coating method using a planetary ball mill. Several mixtures composed of water-soluble additives (D-mannitol, lactose, and erythritol), light anhydrous silicic acid, and flurbiprofen were prepared. These mixtures and several starches were co-ground in a planetary ball mill, and the surface of the starches was dry coated with the mixtures. The size, appearance, yield, and drug dissolution property of the dry coated preparations were evaluated, and the optimal formulation which improved the dissolution property of poorly water-soluble flurbiprofen was determined. The dissolution rate of FP was increased by dry coating of the surface of starches with microparticulated FP. It was further increased by co-grinding of FP, starch, and a water-soluble additive, or dry coating of the starch surface with microparticulated FP and light anhydrous silicic acid, as a glidant. These co-ground and dry coated preparations could be recovered from the pot of the planetary ball mill readily without adhesion to the inside wall of the pot. These are considered to be novel, industrially applicable methods for improving the dissolution rate of poorly water-soluble drugs.     

Investigation of the crystallinity of sugar alcohols co-ground with polymeric excipients

Particle size reducing methods demand high energy input, so during these procedures crystallinity change always can occur. These changes can be enhanced by additives, which are often used to improve the dissolution, the powder rheological properties or the processability of the API (active pharmaceutical ingredient), or to support the particle size reduction. Different materials act differently during these crystallinity changing methods: some materials are easy to amorphize, while some of them can be really resistant. In this work, two chemically equivalent sugar alcohols as model materials—β-d-mannitol as poor glass former and d-sorbitol as good glass former—were chosen to be co-ground with polymeric additives (PVP C30 and PEG 6000). During the 120 min milling process mannitol showed just minor change in crystallinity alone or with PEG. But milled with PVP some amorphization was found. Sorbitol suffered noteworthy changes in crystallinity: raw sorbitol lost its crystallinity during the milling, and also polymorphic transition was displayed. Same transition happened during the milling with PVP: the whole crystallinity of the sorbitol decreased, while the amount of gamma polymorph increased. During the co-grinding with PEG, the polymer prevented the amorphization of sorbitol and kept the well-ordered crystal structure of the material.     

Poly(vinyl pyrrolidone)–poloxamer-188 solid dispersions prepared by hot melt extrusion

Poly(vinyl pyrrolidone) (PVP)/poloxamer-188 blends were used as appropriate carriers for the preparation of solid dispersions by hot melt extrusion using aripiprazole (ARIP) as a poor water-soluble model drug. The physical state of ARIP in solid dispersions and its dissolution characteristics were tested for different drug contents and various PVP-to-poloxamer ratios. From TG analysis it was found that all materials were stable at the tested extrusion temperature conditions (110–120 °C) while amorphous drug dispersions were prepared in all cases, due to the miscibility of the polymer matrix with ARIP drug. Furthermore, hydrogen bonds were identified between ARIP (>N–H) and PVP (>C=O) using FT-IR analysis. Finally, ARIP dissolution rate from SDs was pH dependant and increased as the drug content decreased.     

Improvement of the dissolution rate of nitrendipine using a new pulse combustion drying method

Solid dispersions (SDs) of nitrendipine (NTD), a poorly water-soluble drug, were prepared with the Hypulcon pulse combustion dryer system, and the physicochemical properties of particles were investigated and compared with those of particles prepared with a spray dryer. The SD particles prepared with Hypulcon using Aerosil and Tween 80 as carriers showed improved properties over those prepared with a conventional spray dryer, such as smaller particle size, tighter particle size distribution, and no agglomeration. Powder X-ray diffraction and differential scanning calorimetry evaluation showed that the drug in the NTD-Aerosil SD prepared with 5% (v/v) Tween 80 solution was dispersed in an amorphous state. Fourier transformation IR spectroscopy indicated the presence of hydrogen bonds between NTD and Aerosil. Aerosil had greater ability to improve the dissolution of NTD than Sylysia and other polymers. The highest drug supersaturation concentration was maintained continuously during the dissolution test of the NTD-Aerosil SD prepared with 5% (v/v) Tween 80 solution using Hypulcon. The good hydrophilicity and dispersibility of Aerosil, solubilization of Tween 80, and actions of shock waves and ultrasonic waves might account for the amorphization of NTD and improved dissolution rate of SDs. Pulse combustion drying with low drying costs and high thermal efficiency is a promising method for the preparation of SD particles with improved properties without using organic solvent.     

Physical and chemical changes of medicinals in mixtures with adsorbents in the solid state. II. Application of reduced pressure treatment for the improvement of dissolution of flufenamic acid

Flufenamic acid (FFA) was mixed with magnesium aluminum silicate (MAS) and stored at 60 degrees C at a reduced pressure of about 2.5 mmHg. After storage, when its concentration was not more than 20%, FFA was observed by X-ray diffraction and polarizing microscopy to be amorphous. The dissolution of FFA was thus enhanced in comparison with that of a freshly prepared mixture. Furthermore, the dissolution curves showed a typical supersaturation pattern, and the supersaturation state continued longer, the higher the pH value of the dissolution medium. Flufenamic acid, in a mixture with MAS, became amorphous more rapidly at reduced pressure than at atmospheric pressure, and therefore the effect of improved dissolution appeared earlier at reduced pressure. Infrared spectral studies suggested that FFA, after storage at a reduced pressure with MAS, was dispersed monomolecularly in an ionic form. The technique of treating crystalline medicinals, that have poor solubility in water, with adsorbent at reduced pressure may be useful for improving their dissolution characteristics.     

Effects of aging on crystallization, dissolution and absorption characteristics of amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin complex

The effects of storage on the crystallization, dissolution and absorption of tolbutamide from amorphous tolbutamide-2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) complex were investigated, in comparison with those of polyvinylpyrrolidone (PVP) solid dispersion. The amorphous solid complex of tolbutamide with HP-beta-CyD and the solid dispersion of tolbutamide with PVP were prepared by a spray-drying method. During storage, a stable form of tolbutamide (form I) was crystallized from the amorphous PVP dispersion, whereas a metastable form of tolbutamide (form II) was crystallized from the HP-beta-CyD complex. The dissolution rate of tolbutamide from both HP-beta-CyD complex and PVP dispersion was significantly faster than that of tolbutamide alone. However, the dissolution rate from the PVP dispersion markedly decreased with storage, because of the formation of slow dissolving form I crystals. On the other hand, the dissolution rate from the HP-beta-CyD complex was only slightly decreased due to the formation of fast dissolving formII crystals. These in vitro dissolution characteristics were clearly reflected in the in vivo absorption of tolbutamide and the glucose plasma level after oral administration in dogs. The results suggested that HP-beta-CyD is useful not only for converting crystalline tolbutamide to an amorphous substance, but also for maintaining the fast dissolution rate of the drug over a long period. Furthermore, the crystallization of drugs from CyD complexes, with storage, seemed to be different from that involving polymer excipients such as PVP.     

Application of an intensified narrow channel reactor to the aqueous phase precipitation of barium sulphate

A homogeneous liquid phase reaction between barium chloride (BaCl(2)) and sodium sulphate (Na(2)SO(4)) was conducted in a narrow channel reactor to produce barium sulphate (BaSO(4)) precipitate. The effects of channel dimensions and channel residence times on crystal size, crystal size distribution, nucleation rates, crystal morphology and conversion of reactants were investigated at different levels of reactant supersaturation ratio. Our results indicate that the smallest particle sizes are favoured when supersaturation ratios and channel velocities are high. The minimum average particle diameter observed was approximately 0.2 microm in a channel of hydraulic diameter 0.5 mm and length 20 cm at an initial supersaturation ratio of 4483 (0.1 M), which correspond to conditions giving rise to the highest nucleation rates. It has also been observed that particle size depends on the conversion to product, the smallest particles being formed when conversion lies within the range of 30 to 40%. Conversions in excess of 60% have been reached but there is a detectable limiting effect with increased supersaturation and reduced residence times. Experiments conducted at similar levels of supersaturation under stirred tank conditions showed that particle size was consistently larger and particle size distribution was much broader than that achieved in the narrow channel reactor. Scanning electron microscopy (SEM) images of the crystals formed in the narrow channels show that spherical particles dominate in the smallest channels at high velocities whilst coarse, tabular crystals are obtained in the larger channels. Greater tendency to agglomerate is also observed at high supersaturation ratios, after one minute of reaction.     

The Effect of the Molecular Weight of Polyvinylpyrrolidone and the Model Drug on Laser-Induced In Situ Amorphization

Laser radiation has been shown to be a promising approach for in situ amorphization, i.e., drug amorphization inside the final dosage form. Upon exposure to laser radiation, elevated temperatures in the compacts are obtained. At temperatures above the glass transition temperature (T_g) of the polymer, the drug dissolves into the mobile polymer. Hence, the dissolution kinetics are dependent on the viscosity of the polymer, indirectly determined by the molecular weight (M_w) of the polymer, the solubility of the drug in the polymer, the particle size of the drug and the molecular size of the drug. Using compacts containing 30 wt% of the drug celecoxib (CCX), 69.25 wt% of three different M_w of polyvinylpyrrolidone (PVP: PVP12, PVP17 or PVP25), 0.25 wt% plasmonic nanoaggregates (PNs) and 0.5 wt% lubricant, the effect of the polymer M_w on the dissolution kinetics upon exposure to laser radiation was investigated. Furthermore, the effect of the model drug on the dissolution kinetics was investigated using compacts containing 30 wt% of three different drugs (CCX, indomethacin (IND) and naproxen (NAP)), 69.25 wt% PVP12, 0.25 wt% PN and 0.5 wt% lubricant. In perfect correlation to the Noyes–Whitney equation, this study showed that the use of PVP with the lowest viscosity, i.e., the lowest M_w (here PVP12), led to the fastest rate of amorphization compared to PVP17 and PVP25. Furthermore, NAP showed the fastest rate of amorphization, followed by IND and CCX in PVP12 due to its high solubility and small molecular size.     

Crystallisation of zeolite mordenite and ZSM-5 without the aid of a template

A complex of tenoxicam with-cyclodextrin was prepared by using co-grinding and freeze drying methods. The resulting products were studied by the solubility method, ultraviolet and infrared spectroscopy, differential scanning calorimetry and X-ray diffractometry. The dissolution behaviour of the products was also examined. The dissolution rate of the co-ground and freeze-dried products was faster than that of the pure drug and the physical mixture of drug and-cyclodextrin. The enhanced dissolution rate of the products might be attributed to the amorphous state, the increased wettability of the drug and the inclusion complex formation.     

Preparation and evaluation of solid dispersions of nitrendipine prepared with fine silica particles using the melt-mixing method

Solid dispersions (SD) of nitrendipine (NTD), a poorly water-soluble drug, were prepared using the melt-mixing method with hydrophilic silica particles (Aerosil and Sylysia) with different particle size and specific surface areas as carriers. Powder X-ray diffraction and differential scanning calorimetry evaluation showed that NTD in the SDs treated with the melt-mixing method was dispersed in the amorphous state. FT-IR spectroscopy obtained with the SDs indicated the presence of hydrogen bonding between the secondary amine groups of NTD and silanol groups of silica particles. The dissolution property of NTD in the SDs was remarkably improved regardless of the grade of silica. At the end of the dissolution test (60 min) the concentrations of NTD for the SDs with Aerosil 200 and Sylysia 350 were 8.88 and 10.09 microg/ml, corresponding to 28 and 31 times that of the original NTD crystals, respectively. The specific surface area and the adsorbed water amount of the SDs were also significantly improved. The rapid dissolution rate from the SDs was attributed to the amorphization of drug, improved specific surface area and wettability than the original drug crystals. In the stability test, powder X-ray diffraction pattern indicated that amorphous NTD in the SD with Aerosil 200 was stable for at least 1 month under the humid conditions (40 degrees C/75% RH).     

Enhancement of dissolution rate of valdecoxib by solid dispersions technique with PVP K 30 & PEG 4000: preparation and in vitro evaluation

Solid dispersions of valdecoxib were prepared with the objective of dissolution enhancement by melt granulation technique using polyvinyl pyrollidone (PVP K 30) and polyethylene glycol (PEG 4000) alone (1:1) and in combination (1:0.5:0.5). Phase solubility studies showed a linear increase in valdecoxib solubility with increase in polymer concentration in both the cases. The FTIR spectroscopic studies showed the stability of valdecoxib and absence of well defined valdecoxib—PVP K 30–PEG 4000 interaction. Powder X-ray diffraction (XRD) and differential scanning calorimeter (DSC) were used to characterize the solid state of the dispersion, indicated a complete transformation of drug from crystalline to amorphous form. In vitro dissolution studies performed in 0.1 N HCl showed a significant enhance in dissolution rate when PEG 4000 and PVP K 30 were used in combination. Improved drug dissolution by both the carriers may be attributed to the improved wettability, reduction in drug crystallinity and solubilizing effects from solid dispersions of valdecoxib. Accelerated stability studies of solid dispersion with PVP K 30 and PEG 4000 does not show any significant change in the drug content and dissolution profile in 6 months study period. This study concluded that the dissolution rate of valdecoxib can be modulated by appropriate levels of hydrophilic carriers.     

Characterization of solid dispersions of rofecoxib using differential scanning calorimeter

Summary Solid dispersions were prepared to enhance the dissolution rate of rofecoxib. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used for the characterization of solid dispersions of polyvinyl pyrrolidone (PVP):talc:drug (3:1:1) and hydroxypropyl methylcellulose (HPMC):talc:drug (4:1:1). The DSC study indicated that PVP solid dispersion showed formation of fusion solution while HPMC solid dispersion showed no intermolecular fusion during the preparation of solid dispersions by spray dry process. The dissolution profiles and the calculated times for 75 and 90% drug release showed that dissolution rate of rofecoxib was improved in solid dispersions as compared to pure drug and physical mixtures. The DSC and XRD were successfully employed to find out the crystalline state of drug in the both solid dispersions. PVP solid dispersion gave better dissolution rate than HPMC solid dispersion. The drug was transformed from crystalline to amorphous form in PVP solid dispersion which was further conformed by XRD and DSC. The PVP:talc:drug solid dispersion can be used for the dissolution enhancement and thereby bioavailability of rofecoxib.     

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.     

Enhanced dissolution of oxcarbazepine microcrystals using a static mixer process

The purpose of this study was to form micronized powders of Oxcarbazepine (OXC), a poorly water-soluble drug, using a static mixer technique to enhance the dissolution rate. Controlled precipitation was achieved injecting the organic OXC solution rapidly into an aqueous methylcellulose (MC) protective solution by means of a static mixer thus providing turbulent and homogeneous mixing. Furthermore, a factorial design was implemented for data analysis. The physicochemical properties of the freeze-dried dispersions were evaluated by differential scanning calorimetry (DSC), infrared spectroscopy (FTIR) and X-ray diffraction (XRD). Drug microcrystals showed a narrow size distribution with approximately 2 μm mean particle size and high drug loading. DSC and FTIR studies revealed that the drug remained in crystalline state and no drug–polymer interaction occurred. The dissolution studies showed enhanced dissolution of OXC microcrystals compared to the pure drug. The static mixer technique was proved capable for micro-sized polymeric particles. This is an inexpensive, less time consuming and fully scalable process for development of poorly soluble drugs.