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1.
Purpose
To improve the pharmaceutical properties of amorphous ciprofloxacin (CIP) succinate salts via formulation as polymer/amorphous salt solid dispersions (ASSDs).Methods
ASSDs consisting of an amorphous CIP/succinic acid 1:1 or 2:1 salt dispersed in PVP or Soluplus were produced by spray drying and ball milling. The solid state characteristics, miscibility, stability, solubility and passive transmembrane permeability of the ASSDs were then examined.Results
The ASSDs had higher glass transition and crystallization temperatures than the corresponding amorphous succinate salts, and were also more stable during long-term stability studies. The results of inverse gas chromatography and thermal analysis indicated that the salts and polymers form a miscible mixture. The solubility of the pure drug in water and biorelevant media was significantly increased by all of the formulations. The permeability of the ASSDs did not differ significantly from that of the amorphous CIP succinate salts, however all samples were less permeable than the pure crystalline drug.Conclusions
The formulation of amorphous CIP succinate salts as ASSDs with polymer improved their long-term stability, but did not significantly affect their solubility or permeability.2.
Purpose
The aims of this study were twofold. First, to evaluate the effectiveness of selected polymers in inhibiting solution crystallization of celecoxib. Second, to compare the release rate and crystallization tendency of celecoxib amorphous solid dispersions (ASDs) formulated with a single polymer, or binary polymer combinations.Methods
The effectiveness of polymers, polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC) or HPMC acetate succinate (HPMCAS), in maintaining supersaturation of celecoxib solutions was evaluated by performing nucleation induction time measurements. Crystallization kinetics of ASD suspensions were monitored using Raman spectroscopy. Dissolution experiments were carried out under non-sink conditions.Results
Pure amorphous celecoxib crystallized rapidly through both matrix and solution pathways. Matrix and solution crystallization was inhibited when celecoxib was molecularly mixed with a polymer, resulting in release of the drug to form supersaturated solutions. Cellulosic polymers were more effective than PVP in maintaining supersaturation. Combining a cellulosic polymer and PVP enabled improved drug release and stability to crystallization.Conclusions
Inclusion of an effective solution crystallization inhibitor as a minor component in ternary dispersions resulted in prolonged supersaturation following dissolution. This study shows the feasibility of formulation strategies for ASDs where a major polymer component is used to achieve one key property e.g. release, while a minor polymer component is added to prevent crystallization.3.
Purpose
The effect of Soluplus on the solid-state characteristics and physical transformation of indomethacin (IMC), saccharin (SAC), IMC-SAC physical mixture, and the previously prepared IMC-SAC co-crystal was investigated after solvent evaporation via air-drying process.Methods
Soluplus with γ-IMC or SAC (weight ratio?=?1:1) was respectively prepared by completely dissolving both components in acetone by ultrasonication, and then evaporated via air-drying process. Soluplus was fully co-dissolved with the previously prepared IMC-SAC co-crystal (procedure I) or completely dissolved together with IMC-SAC physical mixture (procedure II) in acetone by ultrasonication, and then evaporated through air-drying process. The physical stability of both Soluplus/IMC-SAC systems was also carried out under accelerated storage conditions. All the samples were determined by thermoanalytical and FTIR spectroscopic studies with spectral curve-fitting technique.Results
Soluplus caused the amorphous formation of IMC or SAC in the Soluplus solid dispersion, in which the intermolecular hydrogen bonding interaction between SAC and Soluplus occurred. Although Soluplus did not influence the co-crystal formation between IMC and SAC in the solid dispersion, the polymorphic transformation and physical stability of Soluplus/IMC-SAC solid dispersion were markedly influenced by procedures I and II after evaporation via air-drying process.Conclusion
Soluplus influences the amorphous or crystalline IMC-SAC co-crystal formulated in the solid dispersion prepared by procedure I or II via air-drying process. The amorphous IMC-SAC co-crystal in the Soluplus solid dispersion prepared by procedure I gradually transformed to a crystalline IMC-SAC co-crystal after storage at 40?±?2 °C/75?±?5 % RH conditions for 28 days, whereas the crystalline IMC-SAC co-crystal in the Soluplus solid dispersion prepared by procedure II via air-drying process maintained a long-term storage stability.4.
Purpose
The aim of our study was development of advanced third generation Curcumin self microemulsifying composition solid dispersion (Cur SMEC-SD) with high drug loading, improved stability, rapid in-vitro dissolution and enhanced bioavailability for improved therapy of rheumatoid arthritis.Method
The Cur SMEC-SD comprising polymers (KollidonVA64[KVA], Eudragits, HPMC and Soluplus) and self microemulsifying composition of surfactant:co-surfactant:oil were coated onto rapidly disintegrating inert tablet core. SDs evaluated for stability, in-vitro release and bioenhancement.Results
Cur SMEC-SDs exhibited high Cur loading of 45% w/w and microemulsion formation with globule size (~100 nm) irrespective of polymers. Among the polymers, SD with KVA revealed exceptionally low contact angle (7°C) and rapid in-vitro release (t50%-6.45 min). No crystallization was evident as confirmed by SEM, DSC and XRD and is attributed to SMEC aided solubilization/amorphisation, and interaction of KVA with Cur seen in the FTIR spectra. Stability was confirmed as per ICH guidelines. Remarkable bioenhancement with Cur SMEC-SD was confirmed by the > four fold and a two fold compared to Cur and Cur-SD without SMEC respectively. High efficacy?~?80% compared to Indomethacin, seen with rheumatoid arthritis (RA) induced rats coupled with no adverse toxicity.Conclusion
The advanced third generation Cur SMEC-SD presents a practical technological advancement and suggests Cur SMEC-SD as promising alternative for RA therapy.5.
Kohei Tahara Masahiro Nishikawa Ko Matsui Koji Hisazumi Risako Onodera Yuichi Tozuka Hirofumi Takeuchi 《Pharmaceutical research》2016,33(9):2259-2268
Purpose
The aim of this study was to enhance the dissolution and oral absorption of poorly water-soluble active pharmaceutical ingredients (APIs) using nanoparticle suspensions prepared with a PureNano? continuous crystallizer (PCC).Method
Nanoparticle suspensions were prepared with a PCC, which is based on microfluidics reaction technology and solvent–antisolvent crystallization. Phenytoin, bezafibrate, flurbiprofen, and miconazole were used as model APIs. These APIs were dissolved in ethanol and precipitated by the addition of water and polyvinyl alcohol. Batch crystallization (BC) using a beaker was also performed to prepare the suspensions. Both PCC and BC formulations were freeze-dried before being characterized in vitro and in vivo.Results
The particle sizes of the nanoparticle suspensions prepared with the PCC were smaller than those prepared by BC. The dissolution rate of each API in vitro significantly increased after crystallization. Reducing the particle size of either the BC or PCC formulation led to increased API flux across Caco-2 cell monolayers. PCC preparations showed higher plasma concentrations after oral administration, demonstrating the advantages of a fast dissolution rate and increased interaction with the gastrointestinal tract owing to the smaller particle size.Conclusions
PCC can continuously produce nanoparticle APIs and is an efficient approach for improving their oral bioavailability.6.
Sharvil Patil Kumudni Xalxo Kakasaheb Mahadik 《Journal of pharmaceutical innovation》2017,12(4):309-318
Purpose
The objective of the current work was to investigate the influence of electrospray technology using various solvents on polymorphic transformations of carbamazepine (CBZ). CBZ was taken as a model drug for electrospray crystallization owing to its well investigated polymorphic forms.Methods
Saturated CBZ solutions (methanol, ethanol, and 2-propanol) were electrosprayed at 20 kV to obtain CBZ crystals. The electrosprayed crystals from methanol (MCBZ), ethanol (ECBZ), and 2-propanol (PCBZ) were characterized by powder X-ray diffractometry, Fourier-transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy, equilibrium solubility, intrinsic dissolution rate, and stability study.Results
MCBZ exhibited mixture of form I and II of CBZ, whereas mixture of form I, II, and III of CBZ was observed in case of ECBZ. Further, PCBZ contained mixture of form II, III, and IV of CBZ. The order in which reduction in saturation solubility and intrinsic dissolution rate was observed, it can be represented as MCBZ > PCBZ > ECBZ > unprocessed CBZ. Electrospray technology induced polymorphic transformations in CBZ crystals. The said polymorphic transformations were influenced by solvent properties along with an electric charge.Conclusion
Thus electrospray crystallization, a continuous pharmaceutical manufacturing technique, can serve as an alternative for crystallization of API with an ability to modify their physicochemical properties.7.
Manoela K. Riekes Axel Engelen Bernard Appeltans Patrick Rombaut Hellen K. Stulzer Guy Van den Mooter 《Pharmaceutical research》2016,33(5):1259-1275
Purpose
Aiming to improve the dissolution rate of ezetimibe (EZE) and lovastatin (LOV) in a fixed dose combination (FDC), co-amorphous systems and ternary solid dispersions were prepared by quench cooling and spray drying, respectively.Methods
Formulations were characterized through X-ray diffraction, modulated differential scanning calorimetry, infrared spectroscopy, scanning electron microscopy and laser diffraction, and evaluated by ‘in vitro’ dissolution. Stability studies were conducted at different conditions during 30 days with the ternary solid dispersion composed of 75% of Soluplus® (ELS 1:1 75%).Results
Single phase co-amorphous systems made up of the pure drugs were not able to increase the dissolution rate of EZE and LOV. However, ternary solid dispersions achieved high dissolution for both compounds, especially when Soluplus® was used as carrier. The dissolution efficiency increased up to 18 (EZE) and 6 (LOV) times in ternary solid dispersions, compared to the crystalline drugs. ELS 1:1 75% preserved its amorphous state during 30 days, in different stability conditions.Conclusions
A spray dried ternary solid dispersion able to enhance the dissolution rate of two poorly soluble, therapeutically complementary drugs, is reported for the first time. These promising results open new perspectives for the development of more advanced FDCs.8.
Hiroyuki Yoshida Akemi Kuwana Hiroko Shibata Ken-ichi Izutsu Yukihiro Goda 《Pharmaceutical research》2016,33(6):1327-1336
Purpose
To clarify the effects of pump pulsation and flow-through cell (FTC) dissolution system settings on the hydrodynamic properties and dissolution profiles of model formulations.Methods
Two FTC systems with different cell temperature control mechanisms were used. Particle image velocimetry (PIV) was used to analyze the hydrodynamic properties of test solutions in the flow-through dissolution test cell. Two pulsation pumps (semi-sine, full-sine) and a non-pulsatile pump were used to study the effects of varied flows on the dissolution profiles of United States Pharmacopeia standard tablets.Results
PIV analysis showed periodic changes in the aligned upward fluid flow throughout the dissolution cell that was designed to reduce the temperature gradient during pump pulsation (0.5 s/pulse). The maximum instantaneous flow from the semi-sine pump was higher than that of the full-sine pump under all conditions. The flow from the semi-sine wave pump showed faster dissolution of salicylic acid and prednisone tablets than those from other pumps. The semi-sine wave pump flow showed similar dissolution profiles in the two FTC systems.Conclusions
Variations in instantaneous fluid flow caused by pump pulsation that meets the requirements of pharmacopoeias are a factor that affects the dissolution profiles of tablets in FTC systems.9.
Backgrounds
Increase in SP release as a function of hypoxia of the rat carotid body is a tissue response to ischemia that leads to neurogenic inflammation and cognitive deficits. Substance P-mediated inflammation is reported to attenuate the neuroprotective PPAR-γ. This study was undertaken to investigate the effect of aprepitant, a substance P-NK1 receptor antagonist in bilateral carotid artery occlusion (BCCAO)-induced ischaemic brain injury and vascular dementia.Methods
Bilateral carotid artery occlusion was performed in Wistar rats to produce hypoperfusion and ischaemic injury. Dementia was noted by an increase in brain acetylcholinesterase (AChE) activity, and attenuation of learning ability (escape latency time) and memory retention (time spent in target quadrant) using Morris water maze. Oxidative stress was estimated by an increase in thiobarbituric acid reactive substances (TBARS) level and a decrease in reduced glutathione level. Vascular dysfunction was measured by attenuation of acetylcholine-induced endothelium-dependent relaxation (isolated carotid ring preparation), and increased in carotid artery TBARS level. Neurodegeneration was assessed in the hippocampus by H&E staining. Aprepitant and donepezil (positive control) were administered to rats from day 28 to day 42 after BCCAO.Results
Aprepitant (20 and 40 mg/kg) and donepezil (2 mg/kg) significantly improved vascular function, learning and memory ability, and decreases the neuronal cell death, oxidative stress, and ache in BCCAO rats. Donepezil effect was more significant than the low dose of aprepitant on disease markers. However, BADGE (30 mg/kg a, PPAR-γ antagonist) prevented the ameliorative effect of aprepitant.Conclusion
Thus, it may be concluded that aprepitant attenuates vascular dysfunction and dementia in BCCAO rats by activating downstream PPAR-γ.10.
Tochukwu C. Okwuosa Dominika Stefaniak Basel Arafat Abdullah Isreb Ka-Wai Wan Mohamed A. Alhnan 《Pharmaceutical research》2016,33(11):2704-2712
Purpose
The fabrication of ready-to-use immediate release tablets via 3D printing provides a powerful tool to on-demand individualization of dosage form. This work aims to adapt a widely used pharmaceutical grade polymer, polyvinylpyrrolidone (PVP), for instant on-demand production of immediate release tablets via FDM 3D printing.Methods
Dipyridamole or theophylline loaded filaments were produced via processing a physical mixture of API (10%) and PVP in the presence of plasticizer through hot-melt extrusion (HME). Computer software was utilized to design a caplet-shaped tablet. The surface morphology of the printed tablet was assessed using scanning electron microscopy (SEM). The physical form of the drugs and its integrity following an FDM 3D printing were assessed using x-ray powder diffractometry (XRPD), thermal analysis and HPLC. In vitro drug release studies for all 3D printed tablets were conducted in a USP II dissolution apparatus.Results
Bridging 3D printing process with HME in the presence of a thermostable filler, talc, enabled the fabrication of immediate release tablets at temperatures as low as 110°C. The integrity of two model drugs was maintained following HME and FDM 3D printing. XRPD indicated that a portion of the loaded theophylline remained crystalline in the tablet. The fabricated tablets demonstrated excellent mechanical properties, acceptable in-batch variability and an immediate in vitro release pattern.Conclusions
Combining the advantages of PVP as an impeding polymer with FDM 3D printing at low temperatures, this approach holds a potential in expanding the spectrum of drugs that could be used in FDM 3D printing for on demand manufacturing of individualised dosage forms.11.
Anran Hu Chen Chen Michael D. Mantle Bettina Wolf Lynn F. Gladden Ali Rajabi-Siahboomi Shahrzad Missaghi Laura Mason Colin D. Melia 《Pharmaceutical research》2017,34(5):941-956
Purpose
Investigate the extended release behaviour of compacts containing mixtures of hydrophilic HPMC and PEO in hydrating media of differing ionic strengths.Methods
The extended release behaviour of various HPMC:PEO compacts was investigated using dissolution testing, confocal microscopy and magnetic resonance imaging, with respect to polymer ratio and ionic strength of the hydrating media.Results
Increasing HPMC content gave longer extended release times, but a greater sensitivity to high ionic dissolution environments. Increasing PEO content reduced this sensitivity. The addition of PEO to a predominantly HPMC matrix reduced release rate sensitivity to high ionic environments. Confocal microscopy of early gel layer development showed the two polymers appeared to contribute independently to gel layer structure whilst together forming a coherent and effective diffusion barrier. There was some evidence that poorly swollen HPMC particles added a tortuosity barrier to the gel layer in high ionic strength environments, resulting in prolonged extended release. MRI provides unique, non-invasive spatially resolved information from within the HPMC:PEO compacts that furthers our understanding of USP 1 and USP 4 dissolution data.Conclusions
Confocal microscopy and MRI data show that combinations of HPMC and PEO have advantageous extended release properties, in comparison with matrices containing a single polymer.12.
Sharvari Bhagwat Uta Schilling Mong-Jen Chen Xiangyin Wei Renishkumar Delvadia Mohammad Absar Bhawana Saluja Günther Hochhaus 《Pharmaceutical research》2017,34(12):2541-2556
Purpose
The ability of two semi-mechanistic simulation approaches to predict the systemic pharmacokinetics (PK) of inhaled corticosteroids (ICSs) delivered via dry powder inhalers (DPIs) was assessed for mometasone furoate, budesonide and fluticasone propionate.Methods
Both approaches derived the total lung doses and the central to peripheral lung deposition ratios from clinically relevant cascade impactor studies, but differed in the way the pulmonary absorption rate was derived. In approach 1, the rate of in vivo drug dissolution/absorption was predicted for the included ICSs from in vitro aerodynamic particle size distribution and in vitro drug solubility estimates measured in an in vivo predictive dissolution medium. Approach 2 derived a first order absorption rate from the mean dissolution time (MDT), determined for the test formulations in an in vitro Transwell® based dissolution system.Results
Approach 1 suggested PK profiles which agreed well with the published pharmacokinetic profiles. Similarly, within approach 2, input parameters for the pulmonary absorption rate constant derived from dissolution rate experiments were able to reasonably predict the pharmacokinetic profiles published in literature.Conclusion
Approach 1 utilizes more complex strategies for predicting the dissolution/absorption process without providing a significant advantage over approach 2 with regard to accuracy of in vivo predictions.13.
Wiebke Kempin Vanessa Domsta Georg Grathoff Iris Brecht Beatrice Semmling Susan Tillmann Werner Weitschies Anne Seidlitz 《Pharmaceutical research》2018,35(6):124
Purpose
Dissolution speeds of tablets printed via Fused Deposition Modeling (FDM) so far are significantly lower compared to powder or granule pressed immediate release tablets. The aim of this work was to print an actual immediate release tablet by choosing suitable polymers and printing designs, also taking into account lower processing temperatures (below 100°C) owing to the used model drug pantoprazole sodium.Methods
Five different pharmaceutical grade polymers polyvinylpyrrolidone (PVP K12), polyethylene glycol 6000 (PEG 6000), Kollidon® VA64, polyethylene glycol 20,000 (PEG 20,000) and poloxamer 407 were successfully hot-melt-extruded to drug loaded filaments and printed to tablets at the required low temperatures.Results
Tablets with the polymers PEG 6000 and PVP K12 and with a proportion of 10% pantoprazole sodium (w/w) demonstrated a fast drug release that was completed within 29 min or 10 min, respectively. By reducing the infill rate of PVP tablets to 50% and thereby increase the tablet porosity it was even possible to reduce the mean time for total drug release to only 3 min.Conclusions
The knowledge acquired through this work might be very beneficial for future FDM applications in the field of immediate release tablets especially with respect to thermo-sensitive drugs.14.
Surface Enrichment and Depletion of the Active Ingredient in Spray Dried Amorphous Solid Dispersions
Zhen Chen Kuan Yang Chengbin Huang Alan Zhu Lian Yu Feng Qian 《Pharmaceutical research》2018,35(2):38
Purpose
To study the effects of physicochemical properties of drug and polymer, as well as the drug-polymer interactions, on the surface composition of SDDs.Methods
Ethanol solutions containing a model drug (IMC, NMP or FCZ) and a model polymer (PVPK12, PVPK30 or PVP-VA) were spray dried, and the surface composition of SDDs was analyzed by XPS. The surface tensions of pure components and their solutions were measured using Wilhelmy plate and/or calculated using ACD/Labs. NMR and DLS were used to obtain the diffusion coefficients of IMC, NMP, PVPK12 and PVPK30 in solvents. Flory-Huggins interaction parameters for selected drug-polymer pairs were obtained using a melting point depression method.Results
Significant surface enrichment or depletion of the drug was observed in SDDs depending on the particular drug-polymer combination. With PVP as the dispersion polymer, IMC and NMP were surface enriched; whereas FCZ, a hydrophilic drug, was surface depleted. With increasing PVP molecular weight, the surface drug concentration increased, and the effect was greater in the NMP/PVP and FCZ/PVP systems than in the IMC/PVP system where strong drug-polymer interaction existed. Changing the polymer from PVP to PVP-VA reduced the surface concentration of the drug.Conclusions
The surface concentration of a SDD can be significantly different from the bulk concentration. The main results of this work are consistent with the notion that the relative surface tensions control surface enrichment or depletion. Besides, the relative diffusion rates of the components and the strength of their interactions may also affect the surface composition of the SDDs.15.
Pei T. Mah Dunja Novakovic Jukka Saarinen Stijn Van Landeghem Leena Peltonen Timo Laaksonen Antti Isomäki Clare J. Strachan 《Pharmaceutical research》2017,34(5):957-970
Purpose
To investigate the effect of compression on the crystallization behavior in amorphous tablets using sum frequency generation (SFG) microscopy imaging and more established analytical methods.Method
Tablets containing neat amorphous griseofulvin with/without excipients (silica, hydroxypropyl methylcellulose acetate succinate (HPMCAS), microcrystalline cellulose (MCC) and polyethylene glycol (PEG)) were prepared. They were analyzed upon preparation and storage using attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy, scanning electron microscopy (SEM) and SFG microscopy.Results
Compression-induced crystallization occurred predominantly on the surface of the neat amorphous griseofulvin tablets, with minimal crystallinity being detected in the core of the tablets. The presence of various types of excipients was not able to mitigate the compression-induced surface crystallization of the amorphous griseofulvin tablets. However, the excipients affected the crystallization rate of amorphous griseofulvin in the core of the tablet upon compression and storage.Conclusions
SFG microscopy can be used in combination with ATR-FTIR spectroscopy and SEM to understand the crystallization behaviour of amorphous tablets upon compression and storage. When selecting excipients for amorphous formulations, it is important to consider the effect of the excipients on the physical stability of the amorphous formulations.16.
Purpose
Molecular understanding of phase stability and transition of the amorphous state helps in formulation and manufacturing of poorly-soluble drugs. Crystallization of a model compound, 2-phenylamino nicotinic acid (2PNA), from the amorphous state was studied using solid-state analytical methods. Our previous report suggests that 2PNA molecules mainly develop intermolecular –COOH???pyridine N (acid-pyridine) interactions in the amorphous state. In the current study, the molecular speciation is explored with regard to the phase transition from the amorphous to the crystalline state.Methods
Using spectroscopic techniques, the molecular interactions and structural evolvement during the recrystallization from the glassy state were investigated.Results
The results unveiled that the structurally heterogeneous amorphous state contains acid-pyridine aggregates – either as hydrogen-bonded neutral molecules or as zwitterions – as well as a population of carboxylic acid dimers. Phase transition from the amorphous state results in crystal structures composed of carboxylic acid dimer (acid-acid) synthon or acid-pyridine chains depending on the crystallization conditions employed.Conclusions
The study underlines the structural evolvement, as well as its impact on the metastability, of amorphous samples from local, supramolecular assemblies to long-range intermolecular ordering through crystallization.17.
Vasanti Suvarna Apeksha Kajwe Manikanta Murahari Gurubasavaraj V. Pujar Bharath Kumar Inturi Atul P. Sherje 《Journal of pharmaceutical innovation》2017,12(2):168-181
Purpose
The objective of present study was to increase solubility and dissolution performance of a poorly water soluble antidiabetic drug, Nateglinide (NAT), through formation of inclusion complexes with hydroxypropyl-beta-cyclodextrin (HP–β–CD). The effect of L-arginine (ARG), an amino acid, on the complexation efficiency and solubility enhancing power of HP–β–CD was investigated by preparing ternary inclusion complexes.Methods
The binary and ternary inclusion complexes were prepared by physical mixing, kneading, co-evaporation, and spray drying methods containing NAT, HP–β–CD, and ARG. The complexes were characterized by FTIR, DSC, PXRD, and 1H–NMR. Molecular modeling study revealed that introduction of ternary agent ARG have improved the interactions of NAT and HP–β–CD.Results
The complex prepared by spray drying method showed the highest increase in solubility and dissolution rate compared to other methods. Molecular docking study revealed that ARG interactions plays an essential role in increasing the stability and solubility of the complex.Conclusions
The present study demonstrated increase in solubility and dissolution of NAT. Hence, ternary complexes of NAT can be used as an efficient tool for the delivery of insoluble drug, NAT.18.
Background
The search for a simple and scalable approach that can improve the two key biopharmaceutical processes (solubility and permeability) for BCS Class II and BCS Class IV has still been unmet need.Purpose
In this study, L-lysine was investigated as a potential excipient to tackle problems with solubility and permeability. Bendazac (Class II); quercetin and rutin (Class IV) were employed.Methods
Drugs-lysine complexes in 1:1 M ratios were prepared by co-precipitation and co-grinding; characterized for solubility, partition coefficient, DSC, FTIR, SEM, dissolution rate and permeability. Chemical stability of quercetin-lysine and rutin-lysine was studied by assessing antioxidant capacity using Trolox and CUPRAC assays.Results and Conclusion
Drugs-lysine salt/complexes were confirmed. Solubility enhancement factors ranged from 68- to 433-fold increases and dissolution rates were also significantly enhanced by up to 6-times, compared with drugs alone. With the exception of rutin-lysine, Papp for bendazac-lysine and quercetin-lysine enhanced by 2.3- to 4-fold. Papp for quercetin (Class IV) benefited more than bendazac (Class II) when complexed with lysine. This study warrants the use of L-lysine as a promising excipient for enhanced solubility and permeability of Class II and Class IV, providing that the solubility of the drug is ensured at ‘the door step’ of absorption sites.19.
Sara B. E. Andersson Caroline Alvebratt Christel A. S. Bergström 《Pharmaceutical research》2017,34(9):1805-1816
Purpose
To develop a small-scale set-up to rapidly and accurately determine the intrinsic dissolution rate (IDR) and apparent solubility of poorly water-soluble compounds.Methods
The IDR and apparent solubility (Sapp) were measured in fasted state simulated intestinal fluid (FaSSIF) for six model compounds using wet-milled controlled suspensions (1.0% (w/w) PVP and 0.2% (w/w) SDS) and the μDISS Profiler. Particle size distribution was measured using a Zetasizer and the total surface area was calculated making use of the density of the compound. Powder and disc dissolution were performed and compared to the IDR of the controlled suspensions.Results
The IDR values obtained from the controlled suspensions were in excellent agreement with IDR from disc measurements. The method used low amount of compound (μg-scale) and the experiments were completed within a few minutes. The IDR values ranged from 0.2–70.6 μg/min/cm2 and the IDR/Sapp ratio ranged from 0.015 to 0.23. This ratio was used to indicate particle size sensitivity on intestinal concentrations reached for poorly water-soluble compounds.Conclusions
The established method is a new, desirable tool that provides the means for rapid and highly accurate measurements of the IDR and apparent solubility in biorelevant dissolution media. The IDR/Sapp is proposed as a measure of particle size sensitivity when significant solubilization may occur.20.