Browsing by Author "Li, M."

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    Apigenin Cocrystals: From Computational Prescreening to Physicochemical Property Characterization
    (ACS Publications, 2023-04-12) Makadia, Jay; Seaton, Colin C.; Li, M.
    Apigenin (4’,5,7-trihydroxyflavone, APG) has many potential therapeutic benefits, however, its poor aqueous solubility has limited its clinical applications. In this work, a large scale cocrystal screening has been conducted, aiming to discover potential APG cocrystals for enhancement of its solubility and dissolution rate. In order to reduce the number of the experimental screening tests, three computational pre-screening tools, i.e., molecular complementarity (MC), hydrogen bond propensity (HBP) and hydrogen bond energy (HBE), were used to provide an initial selection of 47 coformer candidates, leading to discovery of seven APG cocrystals. Among them, six APG cocrystal structures have been determined by successful growth of single crystals, i.e., apigenin-carbamazepine hydrate 1:1:1 cocrystal, apigenin-1,2-di(pyridin-4-yl)ethane hydrate 1:1:1 cocrystal, apigenin-valerolactam 1:2 cocrystal, apigenin-(DL) proline 1:2 cocrystal, apigenin-(D) proline/(L) proline 1:1 cocrystal. All of the APG cocrystals showed improved dissolution performances with potential to be formulated into drug products.
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    Artemisinin Cocrystals for Bioavailability Enhancement. Part 1: Formulation Design and Role of the Polymeric Excipient
    (ACS Publications, 2021-11-01) Kaur, Manreet; Yardley, Vanessa; Wang, Ke; Masania, Jinit; Botana, Adolfo; Arroo, R. R. J.; Li, M.
    Artemisinin (ART) is a most promising antimalarial agent, which is both effective and well-tolerated in patients, though it has therapeutic limitations due to its low solubility, bioavailability and short half-life. The objective of this work was to explore the possibility of formulating ART cocrystals, i.e., artemisinin-orcinol (ART-ORC) and artemisinin-resorcinol (ART2-RES) as oral dosage forms to deliver ART molecules for bioavailability enhancement. This is the first part of the study, aiming to develop a simple and effective formulation which can then be tested on an appropriate animal model (i.e. mouse selected for in vivo study) to evaluate their preclinical pharmacokinetics for further development. In the current work, the physicochemical properties (i.e., solubility and dissolution rate) of ART cocrystals were measured to collect information necessary for the formulation development strategy. It was found that the ART solubility can be increased significantly by its cocrystals, i.e., 26-fold by ART-ORC and 21-fold by ART2-RES respectively. Screening a set of polymers widely used in pharmaceutical products, including Polyvinylpyrrolidone, Hydroxypropyl Methylcellulose and Hydroxypropyl Methylcellulose Acetate Succinate, based on the powder dissolution performance parameter analysis, revealed that Polyvinylpyrrolidone/vinyl Acetate (PVP-VA) was the most effective crystallisation inhibitor. The optimal concentration of PVP-VA at 0.05 mg/mL for the formulation was then determined by a dissolution/permeability method which represented a simplified permeation model to simultaneously evaluate the effects of a crystallization inhibitor on the dissolution and permeation performance of ART cocrystals. Furthermore, experiments, including surface dissolution of single ART cocrystals monitored by Raman spectroscopy and SEM and diffusion properties of ART in solution measured by 1H and diffusion-ordered spectroscopy (DOSY) nuclear magnetic resonance (NMR) spectroscopy, provided insight into how the excipient affects the ART cocrystal dissolution performance and bioavailability.
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    Artemisinin Cocrystals for Bioavailability Enhancement: Part 2. In-vivo Bioavailability and PBPK Modelling
    (ACS Publications, 2021-11-08) Kaur, Manreet; Yardley, Vanessa; Wang, Ke; Masania, Jinit; Arroo, R. R. J.; Turner, David B.; Li, M.
    We report the evaluation and prediction of the pharmacokinetic (PK) performance of artemisinin (ART) cocrystal formulations, i.e., 1:1 Artemisinin-Orcinol (ART-ORC) and 2:1 Artemisinin-Resorcinol (ART2-RES), using in vivo murine animal and PBPK (physiological based pharmacokinetic) models. The efficacy of the ART cocrystal formulations along with the parent drug ART were tested in mice infected with Plasmodium berghei. When given at the same dose, the ART-cocrystal formulation showed a significant reduction in parasitaemia at day 4 post infection compared to ART alone. The PK parameters including Cmax (maximum plasma concentration), Tmax (time to Cmax), AUC (area under the curve) were obtained by determining drug concentrations in the plasma using LC-HRMS (Liquid Chromatography-High Resolution Mass Spectrometry), showing enhanced ART levels after dosage with the cocrystal formulations. The dose-response tests revealed that a significantly lower dose of the ART cocrystals in the formulation was required to achieve a similar therapeutic effect as ART alone. A PBPK model was developed using a PBPK mouse simulator to accurately predict the in vivo behaviour of the cocrystal formulations by combining in vitro dissolution profiles with the properties of the parent drug ART. The study illustrated that information from classical in vitro and in vivo experimental investigations of the parent drug of ART formulation can be coupled with PBPK modelling to predict the PK parameters of an ART cocrystal formulation in an efficient manner. Therefore, the proposed modelling strategy could be used to establish in vitro and in vivo correlations for different cocrystals intended to improve dissolution properties and to support clinical candidate selection, contributing to assessment of cocrystal developability and formulation development.
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    Artemisinin-acetylenedicarboxylic acid cocrystal: screening, structure determination, and physicochemical property characterisation
    (Royal Society of Chemistry, 2021-12-23) Makadia, Jay; Madu, Shadrack J; Arroo, R. R. J.; Seaton, Colin Cormack; Li, M.
    Artemisinin is used to treat malaria, even when caused by multi-drug resistant strains of the Plasmodium parasite; the compound also shows good promise as an anti-cancer drug. However, the usage of artemisinin is limited due to its low aqueous solubility. Herein a large scale of cocrystal screening of artemisinin was conducted using both computational and experimental approaches, resulting in a new 2:1 artemisinin and acetylenedicarboxylic acid (ART2-ACA) cocrystal. ART2-ACA crystallises in the P 212121 space group of an orthorhombic system with the cell parameters a = 10.5089 Å, b = 24.083 Å, c = 6.4952 Å. The asymmetric unit of the cocrystal contains two ART molecules and a single ACA molecule, assembled into discrete trimeric units held together by two supramolecular heterosynthons. It was shown that ART2-ACA cocrystals are of higher solubility and faster dissolution rate compared to the parent drug of artemisinin.
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    Assessing Dose‑Exposure–Response Relationships of Miltefosine in Adults and Children using Physiologically‑Based Pharmacokinetic Modeling Approach
    (Springer Nature, 2023-10-10) Madu, Shadrack J.; Wang, Ke; Chirumamilla, Siri Kalyan; Turner, David B.; Steel, Patrick G.; Li, M.
    Objectives: Miltefosine is the frst and only oral medication to be successfully utilized as an antileishmanial agent. However, the drug is associated with diferences in exposure patterns and cure rates among diferent population groups e.g. ethnicity and age (i.e., children v adults) in clinical trials. In this work, mechanistic population physiologically-based pharmacokinetic (PBPK) models have been developed to study the dose-exposure–response relationship of miltefosine in in silico clinical trials and evaluate the diferences in population groups, particularly children and adults. Methods: The Simcyp population pharmacokinetics platform was employed to predict miltefosine exposure in plasma and peripheral blood mononuclear cells (PBMCs) in a virtual population under diferent dosing regimens. The cure rate of a simulation was based on the percentage of number of the individual virtual subjects with AUCd0-28>535 µg⋅day/mL in the virtual population. Results: It is shown that both adult and paediatric PBPK models of miltefosine can be developed to predict the PK data of the clinical trials accurately. There was no signifcant diference in the predicted dose-exposure–response of the miltefosine treatment for diferent simulated ethnicities under the same dose regime and the dose-selection strategies determined the clinical outcome of the miltefosine treatment. A lower cure rate of the miltefosine treatment in paediatrics was predicted because a lower exposure of miltefosine was simulated in virtual paediatric in comparison with adult virtual populations when they received the same dose of the treatment. Conclusions: The mechanistic PBPK model suggested that the higher fraction of unbound miltefosine in plasma was responsible for a higher probability of failure in paediatrics because of the diference in the distribution of plasma proteins between adults and paediatrics. The developed PBPK models could be used to determine an optimal miltefosine dose regime in future clinical trials.
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    Bi-goal evolution for many-objective optimization problems
    (Elsevier, 2015-11) Li, M.; Yang, Shengxiang; Liu, Xiaohui
    This paper presents a meta-objective optimization approach, called Bi-Goal Evolution (BiGE), to deal with multi-objective optimization problems with many objectives. In multi-objective optimization, it is generally observed that 1) the conflict between the proximity and diversity requirements is aggravated with the increase of the number of objectives and 2) the Pareto dominance loses its effectiveness for a high-dimensional space but works well on a low-dimensional space. Inspired by these two observations, BiGE converts a given multi-objective optimization problem into a bi-goal (objective) optimization problem regarding proximity and diversity, and then handles it using the Pareto dominance relation in this bi-goal domain. Implemented with estimation methods of individuals' performance and the classic Pareto nondominated sorting procedure, BiGE divides individuals into different nondominated layers and attempts to put well-converged and well-distributed individuals into the first few layers. From a series of extensive experiments on four groups of well-defined continuous and combinatorial optimization problems with 5, 10 and 15 objectives, BiGE has been found to be very competitive against five state-of-the-art algorithms in balancing proximity and diversity. The proposed approach is the first step towards a new way of addressing many-objective problems as well as indicating several important issues for future development of this type of algorithms.
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    Cocrystallisation of Daidzein with pyridine-derived molecules: Screening, structure determination and characterisation
    (Elsevier, 2020-07-13) Bolus, Linzie; Wang, Ke; Pask, Christopher; Lai, Xiaojun; Li, M.
    Daidzein (7,4' -dihydroxyisoflavone, DAI) is an isoflavone found in soybeans and Pueraria. DAI has potential therapeutic benefits on cancer and osteoporosis yet has quite low solubility, limiting its use. Herein a cocrystal screening of DAI with pyridine-derived molecules, i.e., nicotinamide, isonicotinamide, caffeine, d -Proline, l -Proline and 4,4' -Bipyridine was conducted. A new cocrystal of Daidzein and 4,4' -Bipyridine (DAI-BIP) was successfully generated via grinding and solvent methods. DAI-BIP showed an increased solubility and dissolution rate. In comparison to DAI, there was a 2.03-fold increase of the dissolution performance parameter for DAI-BIP where the concentration observed for DAI quickly reached the equi- librium solubility and continued to reach 1.49 times DAI solubility. A parachute effect was also observed during the dissolution of DAI-BIP, indicating that BIP might be able to maintain the supersaturated state of DAI in solution proving DAI’s ability to form cocrystals of higher solubility and enhanced dissolution properties through co-crystallisation
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    Comparison of particle size distributions measured using different techniques.
    (Taylor & Francis, 2005) Li, M.; Wilkinson, D.; Patchigolla, Kumar
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    Comparison of USP Paddle and Flow-Through Cell Dissolution Methods for Testing Ketoprofen and Acetaminophen from Fixed-Dose Combination Formulations
    (Colegio de Farmaceuticos, 2016) Medina, Raul; Garcia, Claude A.; Hurtado, Marcela; Li, M.; Dominguez-Ramirez, A. M.
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    Determination of particle size distribution from refractive index measurement.
    (Wiley-Blackwell, 2010) Salaoru, T. A.; Nagy, G.; Li, M.
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    Dynamic model analysis of batch fluidised bed dryers.
    (Wiley, 2008) Li, M.; Duncan, Stephen
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    Effects of coformers on phase transformation and release profiles of carbamazepine cocrystals in hydroxypropyl methylcellulose based matrix tablets
    (Elsevier, 2015-02-01) Qiu, S.; Li, M.
    The aim of this study was to investigate the effects of coformers on phase transformation and release profiles of carbamazepine (CBZ) cocrystals in hydroxypropyl methylcellulose (HPMC) based matrix tablets. It has been found that selection of different coformers of saccharin (SAC) and cinnamic acid (CIN) can affect the stability of CBZ cocrystals in solution, resulting in significant differences in the apparent solubility of CBZ. The dissolution advantage of CBZ–SAC cocrystals can only be shown for a short period during dissolution because of the fast conversion to its dihydrate form (DH). HPMC can partially inhibit the crystallisation of CBZ DH during dissolution of CBZ–SAC cocrystal. However, the increased viscosity of HPMC dissolution medium reduced the dissolution rate of CBZ–SAC cocrystals. Therefore the CBZ–SAC cocrystal formulation did not show any significant advantage in CBZ release rate. In contrast the improved CBZ dissolution rate of CBZ–CIN cocrystal can be realised in both solution and formulation due to its high stability. In conclusion, exploring and understanding the mechanisms of the phase transformation of pharmaceutical cocrystals in aqueous medium for selection of lead cocrystals is the key for success of product development.
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    In situ characterisation of pharmaceutical crystallisation using Vis spectroscopy.
    (Wiley-Blackwell, 2010) Nagy, G.; Salaoru, T. A.; Li, M.
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    In situ monitoring of carbamazepine-nicotinamide cocrystal intrinsic dissolution behaviour
    (Elsevier, 2013) Qiao, N.; Wang, K.; Schlindwein, W. S.; Davies, Angela; Li, M.
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    In Vitro Dissolution Studies of Immediate Release and Extended Release Formulation using Flow-through Cell Apparatus 4. Dissolution technologies
    (2014-05) Qiu, S.; Wang, Ke; Li, M.
    The aims of this study were to evaluate the dissolution performance of solid dosage forms using the open and closed modes of the FTC Apparatus 4 under different flow rates and provide examples to demonstrate the advantages of the FTC method, in particular the possibility of changing the pH during experiments, in studying the release mechanisms of extended-release products. Immediate-release (IR) paracetamol and extended-release (ER) theophylline formulations were used in this study. Results from commercially available IR paracetamol tablets using FTC Apparatus 4 have shown similar dissolution behavior in the closed and open systems, reflecting well-maintained apparent sink conditions and controlled hydrodynamics in the test cells. The flow rate of FTC Apparatus 4 significantly affected the disintegration process of IR tablets. This information can be used as a discriminating tool to support formulation development and to set quality control standards and specifications. To mimic the continuous absorption of theophylline during the passage at different pH values through the whole gastrointestinal tract, dissolution tests were conducted using FTC Apparatus 4 with pH-dependent media for three different commercially available theophylline formulations. Two formulations of Uniphyllin 200-mg tablets and Nuelin SA 175-mg tablets provided a constant release rate during the course of medium pH changes, and their release behavior was predicted with accuracy by appropriate mathematical models. However, wide intervariability and biphasic release in the dissolution profiles were found for Slo-Phyllin 125-mg capsules.
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