Nanocrystalline Solid Dispersion Research Articles

Development of posaconazole nanocrystalline solid dispersion: preparation, characterization and in vivo evaluation

Objective Posaconazole (PCZ) is an antifungal drug, which acts by inhibiting the lanosterol-14α-demethylase enzyme. It is a biopharmaceutical classification system class II drug with its bioavailability being limited by poor aqueous solubility. The aim of this study was to improve the oral bioavailability of PCZ by preparing nanocrystalline solid dispersion (NCS). Methods PCZ-NCS was prepared by a combination of precipitation and high-pressure homogenization followed by freeze-drying. Several different surfactants and polymers were screened to produce NCS with smaller particle size and higher stability. Results The optimized NCS formulation containing 0.2% Eudragit S100 and 0.2% SLS was found to provide the average particle size of 73.31 ± 4.7 nm with a polydispersity index of 0.23 ± 0.03. Scanning electron microscopy revealed the preparation of homogeneous and rounded particles. Differential scanning calorimetry and X-ray diffraction confirmed crystalline nature of NCS. Nanonization increased the saturation solubility of PCZ by about 18-fold in comparison with the neat drug. Intrinsic dissolution study showed 93% dissolution of PCZ within the first 10 min. In vivo pharmacokinetic study in Wistar rats showed that Cmax and AUCtotal of PCZ-NCS increased by 2.58- and 2.64-fold compared to the marketed formulation. Conclusion PCZ-NCS formulation presents a viable approach for enhancing the oral bioavailability of PCZ.

Nanocrystalline solid dispersions: an emerging approach for oral bioavailability enhancement of anticancer drugs using lapatinib ditosylate as the case drug

The bioavailability of lapatinib ditosylate, an active anticancer agent against breast neoplasms, is constrained by its poor bioavailability due to poor aqueous solubility. So, the study’s objective was to develop its nanocrystalline solid dispersion (NSD) in order to improve its oral bioavailability. The process of wet media milling followed by lyophilization was used to prepare NSDs of the drug. Using polyvinyl pyrrolidone (PVP), and sodium dodecyl sulfate (SDS) as combination stabilizers, the resultant NSD demonstrated the smallest particle size and a sufficient stability during formulation screening. Differential scanning calorimetry, and powder X-ray diffraction techniques confirmed the crystalline state of the dispersion. Scanning electron microscopic analysis of optimized NSD revealed evenly distributed rod-shaped crystals of lapatinib ditosylate. The molecular-level interaction in the formulated dispersion was confirmed by NMR analysis. The formulated NSD has enhanced aqueous solubility of lapatinib ditosylate, by 3.68 folds. It also exhibited improved drug release as well as enhanced in vitro anticancer activity in the MCF-7 cell line. Similar findings were derived from in vivo pharmacokinetic investigations, where, compared to pure drug, the maximum plasma drug concentration (Cmax), and area under the curve (AUC), of formulated NSD, increased by 2.45, and 2.56, times respectively for lapatinib ditosylate. All these pharmacokinetic parameters were found to be improved in formulation LP, when compared to the marketed formulation, Tykerb. Thus, this study demonstrated a commercially viable method for increasing the oral bioavailability of anticancer drug, lapatinib ditosylate through the screening and optimization of stabilizers in nanocrystalline solid dispersion.

Rubusoside As a Multifunctional Stabilizer for Novel Nanocrystal-Based Solid Dispersions with a High Drug Loading: A Case Study

The oral bioavailability of poorly soluble drugs has always been the focus of pharmaceutical researchers. We innovatively combined nanocrystal technology and solid dispersion technology to prepare novel nanocrystalline solid dispersions (NCSDs), which enable both the solidification and redispersion of nanocrystals, offering a promising new pathway for oral delivery of insoluble Chinese medicine ingredients. The rubusoside (Rub) was first used as the multifunctional stabilizer of novel apigenin nanocrystal-based solid dispersions (AP-NSD), improving the in vitro solubilization rate of the insoluble drug apigenin(AP). AP-NSD has been produced using a combination of homogenisation and spray-drying technology. The effects of stabilizer type and concentration on AP nanosuspensions (AP-NS) particles, span, and zeta potential were studied. And the effects of different types of protective agents on the yield and redispersibility of AP-NSD were also studied. Furthermore, AP-NSD was characterized by infrared spectroscopy (IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). Solubility was used to assess the in vitro dissolution of AP-NSD relative to APIs and amorphous solid dispersions (AP-ASD), and AP-ASD was prepared by the solvent method. The results showed that 20% Rub stabilized AP-NSD exhibited high drug-loading and good redispersibility and stability, and higher in vitro dissolution rate, which may be related to the presence of Rub on surface of drug. Therefore provides a natural and safe option for the development of formulations for insoluble drugs.

Novel nano-crystalline solid dispersion of nobiletin with improved dissolution behavior and oral absorption

The present study aimed to develop a novel formulation of nobiletin (NOB, a citrus polymethoxylated flavone) by nano-crystalline solid dispersion (nCSD) approach for improving dissolution behavior and oral absorption. NOB-loaded nCSD (nCSD/NOB) was prepared by a wet-milling and freeze-drying systems. Physicochemical properties of nCSD/NOB were characterized in terms of crystallinity, dissolution behavior, particle size distribution, and surface morphology. An analytical method was developed and validated, and a pharmacokinetic study was conducted after oral administration of nCSD/NOB to rats. NOB particles in nCSD/NOB appeared to be crystalline, and the mean diameter was calculated to be ca. 120 nm. In water and acidic condition (pH 1.2), dissolution rates of NOB in nCSD/NOB were ca. 31- and 32-fold higher than those in crystalline NOB, respectively. After oral administration of nCSD/NOB (20 mg-NOB/kg) to rats, nCSD/NOB showed enhanced exposure of NOB compared with crystalline NOB, as evidenced by 12-fold increase of Cmax. The absolute oral bioavailability of NOB in nCSD/NOB was calculated to be ca. 13%, showing 15-fold enhancement compared with that in crystalline NOB. From these findings, the nCSD approach would be efficacious for improving oral absorption of NOB, leading to its enhanced nutraceutical potential.

Study on Integrated Pharmacokinetics of the Component-Based Chinese Medicine of Ginkgo biloba Leaves Based on Nanocrystalline Solid Dispersion Technology

BackgroundTo improve the dissolution and bioavailability of the component-based Chinese medicine of Ginkgo biloba leaves (GBCCM), a novel nanocrystalline solid dispersion of GBCCM (GBCCM NC-SD) was first prepared.MethodsGBCCM mainly containing high pure flavonoid aglycones (FAs) and terpenoid lactones (TLs) was used as the model drug. PVP K30 and SDS were used as solubilizers, combined stabilizers and carriers, and GBCCM NC-SD was prepared by high-pressure homogenization combined with freeze-dryer. Morphology and crystal characteristic of GBCCM NC-SD were analyzed. The dissolution and bioavailability evaluation were performed to investigate the feasibility of GBCCM NC-SD by in vitro dissolution and in vivo integrated pharmacokinetic models.ResultsAfter homogenizing for 30 cycles under the pressure of 650 bar and freeze-drying, GBCCM NC-SD with uniform quality would be obtained. The particle size, PDI and zeta potential were found to be 335.9 ± 32.8 nm, 0.29 ± 0.02 and −28.4 ± 0.7 mV respectively. Based on charged aerosol detector (CAD) technology, a new chromatographic method for simultaneous detection of eight components in GBCCM was developed. In vitro drug release study showed that the cumulative dissolution of FAs and TLs in GBCCM NC-SD increased from 12.77% to 52.92% (P < 0.01) and 90.91% to 99.21% (P < 0.05) respectively. In comparison with physical mixture of GBCCM and stabilizer (PM), the integrated pharmacokinetics AUC0-t of FAs and TLs in GBCCM NC-SD were significantly increased (P < 0.05), and the T1/2 of TLs was also significantly prolonged (P < 0.05).ConclusionThis study demonstrated that novel GBCCM NC-SD was prepared using Polyvinylpyrrolidone K30 (PVP K30) and Sodium dodecyl sulfate (SDS) as a synergetic stabilizer and also provided a feasible way to improve the dissolution and oral bioavailability of poorly soluble candidate antihypertensive drugs.

Optimization of Particle Properties of Nanocrystalline Solid Dispersion Based Dry Powder for Inhalation of Voriconazole

A one-step spray drying based process was employed to generate ready-to-use nanocrystalline solid dispersion (NCSD) dry powder for inhalation (DPI) of voriconazole (VRC). The solid dispersion was prepared by spray drying VRC, MAN (mannitol) and soya lecithin (LEC) from mixture of methanol-water. Various formulation and process related parameters were screened, including LEC, inlet temperature, total solid content and feed flow rate to generate particles of geometric size ≤5 µm. Aerosil® 200 was explored as the quaternary excipient either during spray drying or by physically mixing with the optimized ternary NCSD. The powders were extensively characterized for solid form, primary particle size, assay, embedded nanocrystal size, morphology, porosity, density and moisture content. Aerodynamic properties were studied using next generation impactor (NGI), while surface elemental composition and topography were investigated using SEM-EDS (scanning electron microscopy- energy dispersive spectroscopy) and AFM (atomic force microscopy), respectively. At selected inlet temperature of 120 ˚C, total solid content and feed flow rate significantly impacted the size of primary NCSD particles. Size of primary particles increased with increase in total solid content and feed flow rate of the solution. VRC nanocrystals were obtained in polymorphic Form B whereas the matrix of MAN consisted of mixture of polymorphic Forms α, β and δ. SEM-EDS analysis confirmed deposition of Aerosil® 200 on surface of spray dried particles. In addition to increased porosity and reduced density, increase in surface roughness of particles (evident from AFM topographic analysis) contributed to enhanced powder deposition at stages 3 and 4 in NGI. In comparison, physical blending of NCSD with Aerosil® 200 showed improvement in aerosolization due to flow enhancement property.

High dose nanocrystalline solid dispersion powder of voriconazole for inhalation

In the current work, we aimed to deliver high dose of voriconazole (VRC) to lung through dry powder for inhalation (DPIs). Furthermore, the research tested the hypothesis that drug nanocrystals can escape the clearance mechanisms in lung by virtue of their size and rapid dissolution. High dose nanocrystalline solid dispersion (NCSD) based DPI of VRC was prepared using a novel spray drying process. Mannitol (MAN) and soya lecithin (LEC) were used as crystallization inducer and stabilizer, respectively. The powders were characterized for physicochemical and aerodynamic properties. Chemical interactions contributing to generation and stabilization of VRC nanocrystals in the matrix of MAN were established using computational studies. Performance of NCSD (VRC-N) was compared with microcrystalline solid dispersion (VRC-M) in terms of dissolution, uptake in A549 and RAW 264.7 cells. Plasma and lung distribution of VRC-N and VRC-M in Balb/c mice upon insufflation was compared with the intravenous product.In VRC-N, drug nanocrystals of size 645.86 ± 56.90 nm were successfully produced at VRC loading of 45%. MAN created physical barrier to crystal growth by interacting with N- of triazole and F- of pyrimidine ring of VRC. An increase in drug loading to 60% produced VRC crystals of size 4800 ± 200 nm (VRC-M). The optimized powders were crystalline and showed deposition at stage 2 and 3 in NGI. In comparison to VRC-M, more than 80% of VRC-N dissolved rapidly in around 5–10 mins, therefore, showed higher and lower drug uptake into A549 and RAW 264.7 cells, respectively. In contrast to intravenous product, insufflation of VRC-N and VRC-M led to higher drug concentrations in lung in comparison to plasma. VRC-N showed higher lung AUC0-24 due to escape of macrophage clearance.

Novel Nano-Crystalline Solid Dispersion of Nobiletin with Improved Solubility and Oral Absorption

Novel Nano-Crystalline Solid Dispersion of Nobiletin with Improved Solubility and Oral Absorption

Preparation and Characterization of Co-Processed Mannitol and Sorbitol Using NanoCrySP Technology.

Particle engineering of excipients, at sub-particulate level using co-processing, can provide high functionality excipients. NanoCrySP technology has been recently explored as a novel approach for the generation of nanocrystalline solid dispersion of poorly soluble drugs, using spray drying process. The purpose of the present study was to generate co-processed mannitol and sorbitol (SD-CSM) using NanoCrySP technology having similar composition to commercial co-processed excipient (Compressol® SM, CP). The characterization of excipients was performed to evaluate their various physicomechanical properties. The sub-micron crystallite size of sorbitol in the matrix of mannitol was determined using the Williamson-Hall equation and Halder-Wagner equation. The reduction in crystallite size of sorbitol and mannitol, lower melting point, and lower heat of fusion of SD-CSM could be responsible for excellent compactibility, better tabletability, and comparable compressibility with respect to CP. This was confirmed by the compressibility-tabletability-compactibility (CTC) profile and Heckel plot analysis. Overall, SD-CSM generated using NanoCrySP technology improved functionalities of excipients over CP and would be useful for direct compression application.

Generation of Ophthalmic Nanosuspension of Prednisolone Acetate Using a Novel Technology.

Prednisolone Acetate (PAC) is currently marketed as micronized ophthalmic suspension. The microsuspension has poor dose accuracy and efficacy due to aggregation, slow dissolution rate and limited corneal residence. The ophthalmic nanosuspension of PAC shall show enhanced solubility, dissolution rate and corneal adhesion due to small particle size and increased surface area. In the current work, we prepared ophthalmic formulation of PAC using a novel, spray drying based technology. Firstly, PAC nanocrystalline solid dispersions (NCSD) were prepared using Mannitol (MAN) as the crystallization inducing excipient and two separate stabilizers, Polyvinyl Alcohol (PAC_MAN_PVA) and Vitamin E Tocopheryl Polyethylene Glycol Sulphosuccinate (PAC_MAN_TPGS). The NCSD was dispersed in an aqueous vehicle to obtain an ophthalmic nanosuspension. The composition, PAC_MAN_PVA (0.3:0.67:0.03%), was pursued due to absence of crystal growth on storage at 40°C/75%RH for 3months. The resulting nanosuspension showed crystal size, osmolality and viscosity of 590 ± 165nm, 297 ± 6mOsm/L and 11 ± 8cP respectively. In 1%w/v SLS media, the nanosuspension showed rapid and complete dissolution of PAC in 120s. Ex-vivo goat corneal permeation and adhesion study revealed that in comparison to microsuspension, a higher fraction (6.2 times) of nanosuspension adhered to the cornea. Safety studies performed using corneal histopathology and Hen Egg Test- Chorio Allantoic Membrane (HET-CAM) assay showed no physical change in cornea or capillary damage, respectively. The NCSD can be explored for generation of ophthalmically acceptable nanosuspensions of poorly soluble drugs.

Comparison of Downstream Processing of Nanocrystalline Solid Dispersion and Nanosuspension of Diclofenac Acid to Develop Solid Oral Dosage Form.

The conventional “top-down”, “bottom-up” and “combination” approaches of generating drug nanocrystals produce a “nanosuspension” (NS). It requires significant downstream processing for drying the liquid by suitable means followed by its granulation to develop an oral solid dosage form (OSD). In this paper, we used a novel, spray drying-based NanoCrySP technology for the generation of drug nanocrystals in the form of nanocrystalline solid dispersion (NCSD). We hypothesized that the NCSD would require minimal downstream processing since the nanocrystals are obtained in powder form during spray drying. We further compared downstream processing of NS and NCSD of diclofenac acid (DCF) prepared by wet media milling and NanoCrySP technology, respectively. The NS and NCSD were characterized for crystallinity, crystal size, assay and dissolution. The NCSD was physically mixed with 0.3% Aerosil® 200, 1.76% croscarmellose sodium (CCS) and 0.4% sodium stearyl fumarate (SSF) and filled into size 0 hard gelatin capsules. The NS was first wet granulated using Pearlitol® SD 200 (G1 granules) and Celphere® 203 (G2 granules) in a fluidized bed processor, and the resulting granules were mixed using the same extra granular excipients as NCSD and filled into capsules. A discriminatory dissolution method was developed to monitor changes in dissolution behavior due to crystal growth during processing. Cost analysis and comparison of process efficiency was performed using an innovation radar tool. The NS and NCSD were successfully fabricated with a crystal size of 363 ± 21.87 and 361.61 ± 11.78, respectively. In comparison to NCSD-based capsules (65.13%), the G1 and G2 granules showed crystal growth and decrease in dissolution to 52.68% and 48.37%, respectively, in 120 min. The overall cost for downstream processing of NCSD was up to 80% lower than that of NS. An innovation radar tool also concluded that the one-step NanoCrySP technology was more efficient and required less downstream processing than the two-step wet media milling approach for conversion of nanocrystals to OSD.

Role of Surface Characteristics of Mannitol in Crystallization of Fenofibrate During Spray Drying

NanoCrySP™ is a novel spray-drying-based technology for the generation of nanocrystalline solid dispersions of active pharmaceutical ingredients embedded in the matrix of small molecule excipients. Active pharmaceutical ingredient first appears as an amorphous phase, which transforms to crystalline phase during its passage in the drying chamber. Mannitol acts as a crystallization inducer for the intermediate amorphous phase by primary heterogeneous nucleation. Heteronucleation is a surface-assisted phenomenon and surface characteristics of mannitol were hypothesized to play important role. This study investigates the role of surface characteristics of mannitol on crystallization kinetics of amorphous fenofibrate. Crystallization kinetics of amorphous fenofibrate was assessed on 2 surfaces of mannitol having different porosity, roughness, and polarity. Fenofibrate showed faster crystallization in the presence of rougher surface (tind < 1 min) compared with smooth surface (tind = 49.28 min). This was attributed to higher porosity (75%) and surface polarity (~1.25-fold) of rough surface as compared with smooth surface. Polar nature provided primitive sites for faster crystallization of amorphous fenofibrate. These findings can be utilized for generating crystalline solid dispersions using spray drying in the presence of mannitol. The crystalline solid dispersions can be used for the development of oral solid dosage forms.

Evaluation of Different Techniques for Size Determination of Drug Nanocrystals: A Case Study of Celecoxib Nanocrystalline Solid Dispersion.

Celecoxib (CEL) Nanocrystalline Solid Dispersion (CEL_NCSD) was generated by spray drying CEL, mannitol (MAN) and sodium lauryl sulfate (SLS) from a solvent mixture of methanol, acetone and water. The purpose of the work was to determine the size of CEL nanocrystals, investigate agglomeration and inspect dissolution of CEL_NCSD. Size determination was challenging as CEL nanocrystals are embedded in the matrix of MAN. Firstly, neat CEL_NCSD was analyzed using Scherrer equation. Secondly, MAN was dissolved in an aqueous stabilizer medium to selectively measure the size of CEL nanocrystals. Raman Spectra captured in Morphologi G3-ID confirmed the presence of CEL-only particles in the media. This dispersion gave D90 values of 882 ± 170.34 nm in Zetasizer. Discriminatory dissolution studies confirmed total release of 34.61 ± 1.59%, 47.42 ± 0.24%, and 44.61 ± 1.11% at 120 min from a microsuspension (size 3 µm), a nanosuspension (media milled; size 660 nm) and CEL_NCSD, respectively. The dissolution profile of CEL_NCSD was similar to that of a nanosuspension (f2 72.24) instead of a coarse microsuspension. Thus, the present study revealed that optimized sample preparation is critical for the size determination of embedded drug nanocrystals in NCSD. Further, a discriminatory dissolution study substantiated that the size of CEL nanocrystals in CEL_NCSD is well below 1000 nm, thus showing a size-dependent improved dissolution profile.

Enhanced Oral Bioavailability of Celecoxib Nanocrystalline Solid Dispersion based on Wet Media Milling Technique: Formulation, Optimization and In Vitro/In Vivo Evaluation.

Celecoxib (CLX), a selective COX-2 inhibitor, is a biopharmaceutics classification system (BCS) class II drug with its bioavailability being limited by thepoor aqueoussolubility. The purpose of this study was to develop and optimize CLX nanocrystalline(CLX-NC) solid dispersion prepared by the wet medium millingtechnique combined with lyophilizationto enhance oral bioavailability. In formulation screening, the resulting CLX-NC usingpolyvinylpyrrolidone (PVP) VA64 and sodiumdodecyl sulfate (SDS) as combined stabilizers showed the minimum particle size and a satisfactory stability. The formulation and preparation processwere further optimized by central composite experimentaldesign with PVP VA64 concentration (X1), SDS concentration (X2) and milling times (X3) as independent factors and particle size (Y1), polydispersity index (PDI, Y2) and zeta potential (Y3) as response variables. The optimal condition was determined as a combination of 0.75% PVP VA64, 0.11% SDS with milling for 90 min.The particle size, PDI and zeta potential of optimized CLX-NC were found to be 152.4 ± 1.4 nm, 0.191 ± 0.012 and −34.4 ± 0.6 mV, respectively. The optimized formulation showed homogeneous rod-like morphology as observed by scanning electron microscopy and was in a crystalline state as determined by differential scanning calorimetry and powder X-ray diffraction. In a storage stability study, optimized CLX-NC exhibited an excellent physical stability during six months’ storage at both the refrigeration and room conditions. In vivo pharmacokinetic research in Sprague-Dawley ratsdisplayed that Cmax and AUC0–∞ of CLX-NC were increased by 2.9 and 3.1 fold, compared with physical mixture. In this study, the screening and optimizing strategy of CLX-NC formulation represents a commercially viable approach forenhancing the oral bioavailability of CLX.

Factors Affecting Crystallization Kinetics of Fenofibrate and Its Implications for the Generation of Nanocrystalline Solid Dispersions via Spray Drying

The present study investigates the role of formulation and process parameters on solution- and solid-state crystallization kinetics of fenofibrate (FNT) to attain its submicron crystallite size in ...

Effect of surfactants on the molecular mobility and crystallization kinetics of hesperetin

Recent work from our lab studied the generation and performance evaluation of nanocrystalline solid dispersions (NCSDs) of a hesperetin-mannitol-sodium lauryl sulphate (SLS)-dioctyl sodium sulphosuccinate (DOSS) system.

Nanocrystalline solid dispersions (NSD) of hesperetin (HRN) for prevention of 7, 12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer in Sprague-Dawley (SD) rats

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death in females as per the global cancer project (GLOBOCAN 2018) estimates of breast cancer incidence and mortality produced by the International Agency for Research on Cancer (IARC). In 2018, there will be 2,088,849 new cases of breast cancer and 626,679 cases of deaths due to breast cancer in 5 regions (Americas, Africa, Europe, Asia and Oceania) at 20 sites of the world. Epidemiologic studies on diet and cancer have guided the search for some nutraceuticals acting as anti-cancer agents. Hesperetin (HRN), the aglycone of hesperidin, a glycoside found in citrus fruits, has been reported to have anti-cancer effects by apoptosis induction and inhibition of cell proliferation in cancer cells. However, poor solubility of HRN has limited its absorption while deviating from its therapeutic benefit. The present study aimed to develop nanocrystalline solid dispersions (NSD) of HRN and evaluating the oral bioavailability in rats. The study also evaluated the efficacy of NSDs against the carcinogenic activity of DMBA in female rats. NSDs were optimized using design of experiments (DoE) and multivariate analysis (MVA) tools. The optimized NSD formulation showed an average particle size (Zavg) of 558.2 ± 68.1 nm and ~70% release in 30 min. The in vivo pharmacokinetic study also construed remarkable improvement (3.3 and 2.1-fold increase in Cmax and AUC0–∞) in rate and extent of absorption and 4-fold reduction in Tmax by the optimized NSD formulation. In vivo chemoprevention study construed superior efficacy of the NSD formulation by reducing the tumor burden, delaying the onset of tumors and reducing the tumor weight and volume in DMBA-induced breast cancer rats. In conclusion, we present a simple NSD formulation of HRN with enhanced bioavailability and superior chemopreventive efficacy.

Permeability Behavior of Nanocrystalline Solid Dispersion of Dipyridamole Generated Using NanoCrySP Technology.

Nanocrystals research has been an area of significant interest lately, providing oral bioavailability benefits to solubility- and/or dissolution rate-limited drugs. Drug nanocrystals are generated using top-down or bottom-up technologies. Combination technologies (Nanoedge, Nanopure XP and SmartCrystal) have been recently developed to generate nanocrystals of improved properties. Our lab has also contributed in this field by providing a ‘novel’ platform technology, NanoCrySP, for the generation of nanocrystals. NanoCrySP-generated nanocrystals have improved the oral bioavailability of various molecules. In this study, we aim to assess the permeability behavior of nanocrystals generated by NanoCrySP. Three samples of Dipyridamole (DPM) drug were used in this study: (1) DPM (micron-sized powder), (2) nanocrystals of DPM (NS), generated by media milling (as control) and, (3) nanocrystalline solid dispersion containing DPM (NSD) in the matrix of mannitol (MAN), generated using NanoCrySP technology. In vitro (Caco-2 cell lines) and ex vivo (everted gut sac) studies were conducted in this work. Cellular permeability (Papp) from apical-to-basolateral side in Caco-2 cell monolayer was found to be in the order NS > NSD > DPM, which was the same as their apparent solubility values. Higher Papp from a basolateral-to-apical side suggested a significant contribution of the P-gp efflux transport for DPM, while NS exhibited much higher inhibition of the efflux mechanism than NSD. Both NS and NSD showed higher permeation from the jejunum region in the ex vivo everted gut sac study. Interestingly, Papp of NSD was similar to NS in ex vivo everted gut sac model, however, NSD showed higher mucoadhesion than NS and DPM in this study.

Effect of Mannitol on Nucleation and Crystal Growth of Amorphous Flavonoids: Implications on the Formation of Nanocrystalline Solid Dispersion

In this work, we studied crystallization kinetics of amorphous hesperetin (HRN) and naringenin (NRN) alone, and in 1:1 proportion with mannitol at Tg + 15 K. Crystallization rate of NRN was found to be significantly higher than HRN. Mannitol accelerated crystallization of HRN as well as NRN. NRN exhibited higher crystallization rate than HRN, in presence of mannitol, as well. Finke-Watzky model was used to deconvolute the crystallization kinetics data into nucleation and crystal growth rate constant. HRN alone had 9.56 × 10(9) times faster nucleation rate and 1.88 times slower crystal growth than NRN alone. Mannitol increased nucleation and crystal growth rate of HRN as well as NRN. In presence of mannitol, HRN possessed 1.34 × 10(10) times faster nucleation rate and 1.70 times slower crystal growth rate than NRN. Differences in crystallization behavior of HRN and NRN were explained by their thermodynamic properties.

Mechanism of generation of drug nanocrystals in celecoxib: mannitol nanocrystalline solid dispersion

Objective of this work was to understand the mechanism of formation of celecoxib nanocrystals in celecoxib: mannitol nanocrystalline solid dispersion (NSD). Solution of celecoxib and mannitol was spray dried in 1:1 (g:g) proportion to obtain NSD, with average crystallite size of 214.07±45.27nm. Solubility parameters of celecoxib and mannitol were 23.1MPa1/2 and 38.5MPa1/2, respectively, hinting their immiscibility. Formation of nanocrystals during NanoCrySP proceeds via intermediate amorphous form of the drug. Earlier work from our lab on hesperetin-mannitol system, had underlined the role of plasticization of amorphous drug by excipient in the formation of nanocrystals. However, in present case, mannitol failed to plasticize amorphous celecoxib and Tg of amorphous celecoxib (56.8°C) showed a negligible change (54.8°C) in presence of mannitol. However, DSC data also suggested crystallization inducing potential of mannitol on amorphous celecoxib. Polarized light microscopy provided evidence that, mannitol facilitated heterogeneous nucleation of amorphous celecoxib at their interface. Transmission electron microscopy analysis suggested that, mannitol acted as a physical barrier to crystal growth of celecoxib crystallites. Thus, though mannitol did not plasticize amorphous celecoxib, it aided in nanocrystal generation by heterogeneous nucleation and providing physical barrier to crystal growth.