Characterization and in vitro dissolution behaviour of ketoconazole/β- and 2-hydroxypropyl-β-cyclodextrin inclusion compounds

The effect of β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin on the solubility of ketoconazole in different media were studied. A type A_L solubility diagram was obtained for ketoconazole and the two cyclodextrins in buffer solution, pH 5 and pH 6. The stability constants between ketoconazole and the two cyclodextrins were calculated from the phase solubility diagrams. Increased ionization of the imidazole derivative decreased the values of the stability constants. The formation of solid inclusion complexes were experimentally prepared by the kneading and spray-drying techniques. In order to confirm solid complex formation, X-ray diffractometry and differential scanning calorimetry were used. It was found that the spray-drying technique could be used to prepare the amorphous state of drug inclusion complexes. The dissolution rates of ketoconazole from the inclusion complex made by spray-drying were faster than the pure drug, kneading systems and the physical mixtures of drug and cyclodextrins. The enhanced dissolution rate of spray-dried products might be attributed to the decreased particle size, the high-energetic amorphous state and inclusion complex formation.     

Inclusion complex of colchicine in hydroxypropyl-β-cyclodextrin tenders better solubility and improved pharmacokinetics

Context: Colchicine (CLC) causes cell death by destabilizing the tubulin unit. However, it ionizes at physiological pH resultant low bioavailability and therapeutic efficacy.

Objectives: We have attempted to augment the bioavailability of CLC by fabricating the inclusion complex with hydroxypropyl-β-cyclodextrin (HP-β-CD).

Materials and methods: CLC-HP-β-CD inclusion complex was prepared and evaluated with Fourier-transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffractometry, scanning electron microscopy, ¹H nuclear magnetic resonance (¹H NMR) spectroscopy and rotating frame overhauser enhancement spectroscopy (ROESY). Oral bioavailability of CLC-HP-β-CD inclusion complex was analyzed using high performance liquid chromatography method.

Results and discussion: Our phase-solubility data indicated the formation of a stable complex with K_c ~0.31?mM^?1 at pH 7.4. ¹H NMR ascertains that NHCOCH₃ moiety of CLC enters in the HP-β-CD cavity and deshielded the H-3 and H-5 protons. ROESY also correlates the H_f and H_g of CLC with H-3 and H-5 protons of HP-β-CD and indicates that H_f and H_g protons of CLC are present either as cis and/or trans form in CLC-HP-β-CD inclusion complex. Pharmacokinetic studies showed a 1.82-fold increase in absolute bioavailability of CLC upon complexation.

Conclusion: CLC-HP-β-CD inclusion complex may potentially be used as a viable formulation of CLC.     

Solubility and stability of melatonin in propylene glycol and 2-hydroxypropyl-β-cyclodextrin vehicles

The physicochemical properties of melatonin (MT) in propylene glycol (PG) and 2-hydroxypropyl-beta-cyclodextrin (2-HPbetaCD) vehicles were characterized. MT was endothermally decomposed as determined by differential scanning calorimetry (DSC). Melting point and heat of fusion obtained were 116.9+/-0.24 degrees C and 7249+/-217 cal/mol, respectively. MT as received from a manufacture was very pure, at least 99.9%. The solubility of MT in PG solution increased slowly until reaching 40% PG and then steeply increased. Solubility of MT increased linearly as concentration of 2-HPbetaCD without PG increased (R(2)=0.993). MT solubility in the mixtures of PG and 2-HPbetaCD also increased linearly but was less than the sum of its solubility in 2-HPbetaCD and PG individually. The MT solubility was low in water, simulated gastric or intestinal fluid but the highest in the mixture of PG (40 v/v%) and 2-HPbetaCD (30 w/v%) although efficiency of MT solubilization in 2-HPbetaCD decreased as the concentration of PG increased. MT was degraded in a fashion of the first order kinetics (r(2)>0.90). MT was unstable in strong acidic solution (HCl-NaCl buffer, pH 1.4) but relatively stable in other pH values of 4 approximately 10 at 70 degrees C. In HCl-NaCl buffer, MT in 10% PG was more quickly degraded and then slowed down at a higher concentration. However, the degradation rate constant of MT in 2-HPbetaCD was not changed significantly when compared to the water. The current studies can be applied to the dosage formulations for the purpose of enhancing percutaneous absorption or bioavailability of MT.     

Effects of Kollicoat IR® and hydroxypropyl-β-cyclodextrin on the dissolution rate of omeprazole from its microparticles and enteric-coated capsules

Omeprazole microparticles were prepared by different drying techniques using Kollicoat IR^® and hydroxypropyl-β-cyclodextrin hydrophilic polymers. Physico-chemical properties were investigated using differential scanning calorimetry and powder X-ray diffractometry. Dissolution rate was determined and compared to the physical mixtures and the morphology was studied using a scanning electron microscope. Omeprazole transformed from the crystalline state to the amorphous state as confirmed by the disappearance of its melting peak and the characteristic of the crystalline peaks. Omeprazole dissolution rate was enhanced significantly from its spray- and freeze-dried microparticles as compared to the corresponding physical mixtures and drug alone (P?<?0.05). F3 and F5 formula possessed superior release rate over other formulations. In acidic medium, the release of drug from enteric-coated capsules was not detectable, while it is completely released within 40?min after changing dissolution medium to phosphate buffer (pH 7.4). The transformation of OME from crystalline to amorphous state by using either Kollicoat IR^® or hydroxylpropyl-β-cyclodextrin is considered a promising way to improvement of drug dissolution.     

Influence of hydroxypropyl-β-cyclodextrin and dimethyl-β-cyclodextrin on diphenhydramine intestinal absorption in a rat in situ model

The influence of complexation of diphenhydramine (DPHA) with hydroxypropyl-β-cyclodextrin (HPβCD) and dimethyl-β-cyclodextrin (DMβCD) on intestinal absorption of DPHA has been investigated on an in situ model in rats. The mean apparent stability constants of the complexes formed at 23°C between DPHA and the cyclodextrins DMβCD and HPβCD were 4988 and 1635 M⁻¹, respectively. At 37°C, the apparent stability constants were smaller: 895 and 494 M⁻¹ for the complexes formed between DPHA and the cyclodextrins DMβCD and HPβCD, respectively. Complexation of DPHA with DMβCD led to a significant decrease (−36%) in the percentage of DPHA absorbed (30.6±12.0 vs. 22.5±6.9%, P=0.018). On the other hand, complexation of DPHA with HPβCD only slightly decreased (−8%) the extent of absorption (43.2±9.0 vs. 40.0±7.7%, P=0.16). These data suggest that the magnitude of the apparent stability constant of drug–cyclodextrin complexes should be considered when complexes are used to increase the oral absorption of drugs.     

Physicochemical properties of tadalafil solid dispersions – Impact of polymer on the apparent solubility and dissolution rate of tadalafil

To improve solubility of tadalafil (Td), a poorly soluble drug substance (3 μg/ml) belonging to the II class of the Biopharmaceutical Classification System, its six different solid dispersions (1:1, w/w) in the following polymers: HPMC, MC, PVP, PVP-VA, Kollicoat IR and Soluplus were successfully produced by freeze-drying. Scanning electron microscopy showed a morphological structure of solid dispersions typical of lyophilisates. Apparent solubility and intrinsic dissolution rate studies revealed the greatest, a 16-fold, increase in drug solubility (50 μg/ml) and a significant, 20-fold, dissolution rate enhancement for the Td/PVP-VA solid dispersion in comparison with crystalline Td. However, the longest duration of the supersaturation state in water (27 μg/ml) over 24 h was observed for the Td solid dispersion in HPMC. The improved dissolution of Td from Td/PVP-VA was confirmed in the standard dissolution test of capsules filled with solid dispersions. Powder X-ray diffraction and thermal analysis showed the amorphous nature of these binary systems and indicated the existence of dispersion at the molecular level and its supersaturated character, respectively. Nevertheless, as evidenced by film casting, the greatest ability to dissolve Td in polymer was determined for PVP-VA. The crystallization tendency of Td dispersed in Kollicoat IR could be explained by the low T_g (113 °C) of the solid dispersion and the highest difference in Hansen solubility parameters (6.8 MPa^0.5) between Td and the polymer, although this relationship was not satisfied for the partially crystalline dispersion in PVP. Similarly, no correlation was found between the strength of hydrogen bonds investigated using infrared spectroscopy and the physical stability of solid dispersions or the level of supersaturation in aqueous solution.     

Simultaneous determination of danshensu,rosmarinic acid,cryptotanshinone, tanshinone IIA,tanshinone I and dihydrotanshinone I by liquid chromatographic–mass spectrometry and the application to pharmacokinetics in rats

A sensitive and specific liquid chromatography–tandem mass spectrometry method (LC–MS) was developed and validated for the separation and simultaneous determination of danshensu, rosmarinic acid and tanshinone compounds including cryptotanshinone, tanshinone I, dihydrotanshinone I and tanshinone IIA in rat plasma. Chromatographic separation of the analytes was successfully achieved on a C₁₈ column using a mobile phase composed of acetonitrile–water containing 0.5% glacial acetic acid. This method demonstrated good linearity and did not have endogenous material interfering with the active compounds and I.S. peaks. The limit of quantification of danshensu, rosmarinic acid, cryptotanshinone, dihydrotanshinone I, tanshinone I and tanshinone IIA were 5, 0.75, 0.1, 0.1, 1 and 0.5 ng/mL. The average extraction recoveries of these analytes from rat plasma were all over 60%. The precisions determined from five days were all within 10%. This method has been successfully applied in the simultaneous quantification and the pharmacokinetic studies of these six compounds in animals which were orally administered with danshen preparations.     

Enhanced dissolution,stability and physicochemical characterization of ATRA/2-hydroxypropyl-β-cyclodextrin inclusion complex pellets prepared by fluid-bed coating technique

The aim of this work was to prepare stable all-trans-retinoic acid (ATRA)/2-hydroxypropyl-β-cyclodextrin (HPCD) inclusion complex pellets with industrial feasible technology, the fluid-bed coating technique, using PVP K30 simultaneously as binder and reprecipitation retarder. The coating process was fluent with high coating efficiency. In vitro dissolution of the inclusion complex pellets in 5% w/v Cremopher EL solution was dramatically enhanced with no reprecipitation observed, and significantly improved stability against humidity (92.5% and 75% RH) and illumination (4500 lx ± 500 lx) was achieved by HPCD inclusion. Differential scanning calorimetry and powder X-ray diffractometry confirmed the absence of crystallinity of ATRA. Fourier transform-infrared spectrometry revealed interaction between ATRA and HPCD adding evidence on inclusion of ATRA moieties into HPCD cavities. Solid-state ¹³C NMR spectrometry indicated possible inclusion of ATRA through the polyene chain, which was the main reason for the enhanced photostability. It is concluded that the fluid-bed coating technique has the potential use in the industrial preparation of ATRA/HPCD inclusion complex pellets.     

β-cyclodextrin complexes of celecoxib: Molecular-modeling, characterization, and dissolution studies

Celecoxib, a specific inhibitor of cycloxygenase-2 (COX-2) is a poorly water-soluble nonsteroidal anti-inflammatory drug with relatively low bioavailability. The effect of beta-cyclodextrin on the aqueous solubility and dissolution rate of celecoxib was investigated. The possibility of molecular arrangement of inclusion complexes of celecoxib and beta-cyclodextrin were studied using molecular modeling and structural designing. The results offer a better correlation in terms of orientation of celecoxib inside the cyclodextrin cavity. Phase-solubility profile indicated that the solubility of celecoxib was significantly increased in the presence of beta-cyclodextrin and was classified as AL-type, indicating the 1:1 stoichiometric inclusion complexes. Solid complexes prepared by freeze drying, evaporation, and kneading methods were characterized using differential scanning calorimetry, powder x-ray diffractometry, and scanning electron microscopy. In vitro studies showed that the solubility and dissolution rate of celecoxib were significantly improved by complexation with beta-cyclodextrin with respect to the drug alone. In contrast, freeze-dried complexes showed higher dissolution rate than the other complexes.     

Effects of β-cyclodextrin and di-O-methyl-β-cyclodextrin on the percutaneous absorption of butylparaben,indomethacin and sulfanilic acid

The effects of β-cyclodextrin (β-CD) and di-O-methyl-β-cyclodextrin (DM-β-CD) on the percutaneous absorption of butylparaben (BP), indomethacin (IM), and sulfanilic acid (SA) were investigated. The flow-through type diffusion cell was used for in vitro penetration experiments. All of the recorded data were fitted to the diffusion equation describing the drug penetration through a homogeneous plane membrane by the non-linear least-squares computer program, and two parameters corresponding to diffusion constant of drug and partition coefficient of that between skin and vehicle were obtained. Both cyclodextrins (CDs) decreased the penetration of BP depending on their concentrations. The decrease in BP penetration was explained by that in calculated apparent partition coefficient of BP and good correlation was observed between the partition coefficient and free BP fraction estimated based on the complex formation stoichiometry. IM penetration was also decreased by complex formation but some additional effects, somewhat different between β-CD and DM-β-CD, were observed. On the contrary, the penetration of SA which scarcely formed complex with either CD was significantly enhanced by DM-β-CD. This was attributed to the effect of DM-β-CD on the skin to reduce its barrier function.     

Tolerance to the effects of Δ 9-tetrahydrocannabinol in mice on intestinal motility,temperature and locomotor activity

The onset and duration of tolerance to three effects of ⁹-tetrahydrocannabinol ( ⁹-THC) given orally to mice were compared. The effects of ⁹-THC studied were: hypothermia, the depression of intestinal motility and the effect on spontaneous locomotor activity. When mice were dosed and tested at 24 hrs intervals it was apparent that tolerance was complete to its hypothermic and locomotor depressant effects after the first doses and to depression of intestinal motility after the fourth dose. Duration of tolerance also differed so that the normal hypothermic response had returned after 12 dose-free days, but not after 5 drug-free days; the effect on locomotor activity had returned within 4 days; and, apparent partial tolerance to the depressant effect of an acute challenging dose of ⁹-THC on intestinal motility still existed after 19 dose-free days.It is apparent that the time of onset and the duration of tolerance to ⁹-THC in mice showed a different pattern in the three parameters studied. It seems unlikely therefore that any one mechanism, such as metabolic tolerance, explains all the results observed and that several mechanisms should be explored to explain the phenomenon of tolerance to ⁹-THC.     

Effect of 2-Hydroxypropyl-β-cyclodextrin on the Ocular Absorption of Dexamethasone and Dexamethasone Acetate

Complexation of dexamethasone (DX) and dexamethasone acetate (DXA) with 2-hydroxypropyl--cyclodextrin (HPCD) was investigated with an ultimate goal of formulating a topical ophthalmic solution of DXA. Aqueous solubility of DX and DXA was markedly increased due to formation of soluble inclusion complexes with HPCD. Based on characterization of complex formation by phase solubility and UV-spectroscopy methods, a stoichiometry of 1:1 and 1:1, 1:2 was assumed for DX-HPCD and DXA-HPCD complexes, respectively. The stability constants for complex formation estimated by phase solubility and UV-spectroscopy methods, respectively, were as follows: for DX-HPCD complex, K_{l :l} = 2193 and 2221 M^–1; and for DXA-HPCD complex, K _1:1 = 2240 and 2445 M ^–l and K _l:2 = 3 and 17 M ^–1. K _{l :l} of 2266 M ^–l and K _{l :2} of 20 M ^–l were also estimated for the DXA-HPCD complex by kinetics. The kinetics of DXA degradation in pH 7 phosphate buffer at 25°C followed pseudo first order. The addition of HPCD decreased the rate but the order of reaction remained unchanged. Free DXA degraded at a faster rate than complexed DXA. Ocular bioavailability in conjunctiva, cornea, iris, and aqueous humor postadministration of a 25-µl dose of formulations containing an equivalent of 0.1% (w/v) DX followed a rank-order of DXA-HPCD solution > DXA suspension > DX-HPCD solution > DX suspension.     

Insight into the pharmacokinetic behavior of tanshinone IIA in the treatment of Crohn’s disease: comparative data for tanshinone IIA and its two glucuronidated metabolites in normal and recurrent colitis models after oral administration

1.?Previous reports implied that tanshinone IIA (TSA) may offer potential benefits for Crohn’s disease (CD). However, the detailed pharmacokinetic behavior of TSA in the treatment of colitis remain unclear. Herein, a recurrent trinitrobenzene sulfonic acid (TNBS)-colitis mouse model was used to investigate whether TSA possesses favorable pharmacokinetic and colonic distribution profiles to serve as a candidate drug.

2.?Although the systemic TSA exposures were low (AUC_0–t approximately 330?ng*h/ml) in both the normal and colitis models after oral administration TSA 20?mg/kg, high levels of TSA were found in the gastrointestinal tract (GI). Such a GI exposure of TSA in colitis mice is adequate to exert anti-inflammatory effects as observed in various in vitro studies.

3.?Interestingly, colonic TSA exposure in the colitis mouse model was much lower than that in the normal mice, which may be explained by a significant upregulation of colonic UDP-glucuronosyltransferase (Ugt)1a9 expression and a higher plasma concentration of TSA glucuronides in the model mice at 0.5, 1 and 2?h after TSA administration.

4.?Together, these results reveal high accumulation at the site of inflammation and minimal systemic concentration of TSA, which are favorable pharmacokinetic behaviors to meet the requirements for CD treatment.     

Comparative effects ofβ 2-adrenoceptor agonists on intracranial self-stimulation,Sidman avoidance,and motor activity in rats

The effects of -adrenoceptor agonists were compared in various operant behavioral tasks, particularly intracranial self-stimulation (ICSS). Clenbuterol, salbutamol, and terbutaline all reduced responding by rats that lever-pressed for low stimulation intensities. The effects of clenbuterol in this test were completely reversed by propranolol, and those of salbutamol were partly reversed. Intermediate doses of clenbuterol and salbutamol slowed the initiation of rewarding brain stimulation in a shuttlebox but had little or no effect on the termination latencies. However, higher doses of both drugs lengthened the termination latencies. Motor activity was reduced at doses that attenuated ICSS responding. Complete tolerance occurred within 4 days to the effects of clenbuterol and salbutamol on leverpressing ICSS and to the effects of clenbuterol on motor activity. The apparent performance deficits induced by these drugs were overcome by more intense motivation. For example, even at high doses, clenbuterol reduced ICSS leverpressing only partially when animals bar-pressed for high rather than low stimulation intensities. Furthermore, all three drugs failed to alter Sidman avoidance responding at doses up to 100 times those that attenuated ICSS responding. It is concluded that although -adrenoceptor agonists cause apparent sedation in rats, this sedation is limited and shows rapid tolerance.     

Toxic effects of subacute inhalation exposure to trichloroethylene on serum lipid profile,glucose and biochemical parameters in Sprague–Dawley rats

Abstract

The current study evaluated the inhalation toxicity of trichloroethylene (TCE) at 0, 10, 100, 250 and 400?ppm in Sprague–Dawley rats for 10 day period, because the subacute inhalation toxicity of TCE on serum lipid profile, glucose and some biochemical parameters has not been previously reported. TCE vapors were generated using the dynamic generation system based on evaporation method in the exposure chamber. On the basis of the results, mean serum low-density lipoprotein (LDL) and albumin (ALB) decreased significantly in all the groups exposed to TCE compared with the control group (p?<?.005), but there was a significant increase for parameters: fasting blood glucose (FBG) and alkaline phosphatase (ALP) (p?<?.005). Rats exposed to 400?ppm TCE showed a significant decrease in serum cholesterol (CHOL) and protein (Pr) compared with the control group (p?<?.005). A negative relationship was found between triglycerides (TG), very low density lipoprotein (VLDL), CHOL, LDL, Pr, ALB and urea levels and the subacute exposure to concentrations of TCE (R²?=?–0.26, p?<?.05), but there was a direct correlation for parameters FBG, ALP and alanine aminotransferase (ALT) (R²?=?0.42, p?<?.05). In conclusion, studies with Sprague–Dawley rats demonstrated that subacute inhalation exposure to TCE (≥ 100?PPM) is associated with biochemical and lipotoxicity in the form of decreased serum ALB and LDL and raised ALP and glucose levels. The present study also provides additional evidence relating to decreased serum CHOL and Pr after subacute inhalation exposure to 400?ppm TCE.     

Sufentanil-2-hydroxypropyl-β-cyclodextrin inclusion complex for pain treatment: Physicochemical, cytotoxicity, and pharmacological evaluation

Sufentanil (SUF) is a synthetic analgesic opioid widely used for the management of acute and chronic pain. This drug was complexed with 2‐hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) and the physicochemical characterization, in vitro/ex vivo toxicity assays, and pharmacological evaluation were performed. Differential scanning calorimetry, Fourier transform infrared spectroscopy (FTIR) analysis, and X‐ray powder diffraction showed the formation and the morphology of the complex. Nuclear magnetic resonance afforded data regarding inclusion complex stoichiometry (1:1) with an association binding constant (K_a) value of 515.2 ± 1.2 M^?1 between SUF and HP‐β‐CD. Complexation with HP‐β‐CD protected SUF from light exposure and increased its photostability. Release kinetics revealed a decrease in SUF release rate (K_rel = 7.05 ± 0.52 and 5.61 ± 0.39 min^?1/2 for SUF–HP‐β‐CD and SUF, respectively) and reduced hemolytic or myotoxic effects after complexation. Time course of tail‐flick test showed that the duration of analgesia induced by SUF (150.0 ± 34.6 min) was significantly increased (p < 0.001) after complexation with HP‐β‐CD (355.7 ± 47.2 min) when injected at the same dose (1 μg kg^?1), prolonging the duration of analgesia after intramuscular administration and representing an alternative on the development of effective and safe drug‐delivery system for opioid analgesics.     

HP-β-CD-PLGA nanoparticles improve the penetration and bioavailability of puerarin and enhance the therapeutic effects on brain ischemia–reperfusion injury in rats

It is well known that puerarin attenuates ischemia–reperfusion injury and promotes function recovery of ischemic region. However, due to its reverse physiochemical properties, puerarin does not easily cross the blood–brain barrier. The aim of the present study is to create puerarin nanoparticles which increase and prolong the puerarin concentration in the brain. Using emulsion solvent evaporation techniques, we designed puerarin-loaded poly(d,l-lactic-co-glycolic acid) nanoparticles. Hydroxypropyl beta cyclodextrin (HP-β-CD) was used to increase the solubility of puerarin and gelatin to enhance viscosity of inner water phase, which improved puerarin entrapment. The drug release kinetics and nanoparticle degradation in phosphate buffered saline (PBS) were analyzed by electronic microscopy and high-performance liquid chromatography. Computerized tomography scans were used to detect the infarction volume and electroencephalogram (EEG) was recorded to estimate the recovery of brain function. The results showed that the combined HP-β-CD and gelatin significantly improved the entrapment efficiency. The infarction volume was significantly decreased on days 3 and 7 after the administration of puerarin nanoparticles compared with that of control and pure puerarin. EEG was also significantly improved. Puerarin nanoparticles are potentially applicable for the brain injury induced by ischemic–reperfusion.     

The potential therapeutic effects of baicalein and breviscapine on the vascular dementia of rats

Baicalein and breviscapine are traditional Chinese medicines and are extensively used in clinic to treat cardiovascular diseases and cerebrovascular injury. In a series of studies, we demonstrated that both of them have therapeutic effects on cognitive impairment and neuronal degeneration in a rat model of chronic cerebral hypoperfusion induced by permanent occlusion of bilateral common carotid arteries （2VO）.     

Effect of 2-Hydroxypropyl-β-cyclodextrin on Crystallization and Polymorphic Transition of Nifedipine in Solid State

The glassy state of nifedipine (NP) was prepared in the absence and presence of 2-hydroxypropyl--cyclodextrin (HP--CyD), and its crystallization and polymorphic transition behavior was investigated by differential scanning calorimetry (DSC) and powder X-ray diffractometry. In DSC thermograms, the glassy NP exhibited an en-dothermic peak at 48°C representing the glass transition of NP, an exothermic peak at 105°C for the crystallization to a metastable form of NP (Form B), an exothermic peak at 125°C for the polymorphic transition of Form B to a stable form of NP (Form A), and an endothermic peak at 171°C for the melting of Form A. The powder X-ray diffractogram of Form B was apparently different from that of Form A. In the presence of HP--CyD, the exothermic peak at 125°C for the Form B to A transition disappeared and a new en-dothermic peak appeared at 163°C. This new peak was ascribed to the melting of Form B, and the conversion of Form B to Form A was significantly suppressed in HP--CyD matrix. Upon storage at 60°C, the glassy NP was converted to Form A with an activation energy of 18 kcal/mol. The apparent dissolution rate of the NP/HP--CyD (molar ratio 1:1) increased in the order of glassy NP < Form A < Form B, because the glassy NP was readily converted to Form A upon contact with water, resulting in a lower dissolution rate. The present data suggest that HP--CyD is useful for the preparation of a fast dissolving form of metastable NP through glassy NP.