David J. Berry

Pharmaceutical co-crystals – are we there yet?

In the pharmaceutical arena it is agreed that co-crystals form a vital part of the solid-state toolbox, allowing the progression of novel compounds through the development pathway to patients and improving properties in older medicines. Sadly though, few co-crystals have made it to the market in the form of a new licensed product. This displays a disconnect between research effort and end product. For some time now it has been possible to determine the formation of co-crystals, by a variety of screening and analytical means; although it is recognised that there will always be phases that sit in the ‘greyer’ area of the salt-co-crystal continuum. It is also possible, with limitations, to predict the formation of co-crystals in silico via energetic and structural considerations. So what are the major hurdles and missing links, and what are the key structural properties we need to study to improve the success rate? This highlight hopes to address these.

Pharmaceutical cocrystals, salts and multicomponent systems; intermolecular interactions and property based design☆

Abstract As small molecule drugs become harder to develop and less cost effective for patient use, efficient strategies for their property improvement become increasingly important to global health initiatives. Improvements in the physical properties of Active Pharmaceutical Ingredients (APIs), without changes in the covalent chemistry, have long been possible through the application of binary component solids. This was first achieved through the use of pharmaceutical salts, within the last 10–15 years with cocrystals and more recently coamorphous systems have also been consciously applied to this problem. In order to rationally discover the best multicomponent phase for drug development, intermolecular interactions need to be considered at all stages of the process. This review highlights the current thinking in this area and the state of the art in: pharmaceutical multicomponent phase design, the intermolecular interactions in these phases, the implications of these interactions on the material properties and the pharmacokinetics in a patient. Graphical abstract Figure. No Caption available.

Tuning the spontaneous formation kinetics of caffeine:malonic acid co-crystals

It has previously been reported that the caffeine : malonic acid co-crystal system forms spontaneously upon the contact of the two materials. Here we studied the crystal growth in this system to rationally define the role that water plays, thus enabling us to monitor the conversion by solid-state NMR and control the kinetics of spontaneous co-crystal production by increasing or decreasing the relative humidity.

In silico (computed) modelling of doses and dosing regimens associated with morphine levels above international legal driving limits

Background: Morphine can cause central nervous system side effects which impair driving skills. The legal blood morphine concentration limit for driving is 20 µg/L in France/Poland/Netherlands and 80 µg/L in England/Wales. There is no guidance as to the morphine dose leading to this concentration. Aim: The in silico (computed) relationship of oral morphine dose and plasma concentration was modelled to provide dose estimates for a morphine plasma concentration above 20 and 80 µg/L in different patient groups. Design: A dose–concentration model for different genders, ages and oral morphine formulations, validated against clinical pharmacokinetic data, was generated using Simcyp®, a population-based pharmacokinetic simulator. Setting/participants: Healthy Northern European population parameters were used with age, gender and renal function being varied in the different simulation groups. In total, 36,000 simulated human subjects (100 per modelled group of different ages and gender) received repeated simulated morphine dosing with modified-release or immediate-release formulations. Results: Older age, women, modified-release formulation and worse renal function were associated with higher plasma concentrations. Across all groups, morphine doses below 20 mg/day were unlikely to result in a morphine plasma concentration above 20 µg/L; this was 80 mg/day with the 80 µg/L limit. Conclusion: This novel study provides predictions of the in silico (computed) dose–concentration relationship for international application. Individualised morphine prescribing decisions by clinicians must be informed by clinical judgement considering the individual patient’s level of impairment and insight irrespective of the blood morphine concentration as people who have impaired driving will be breaking the law. Taking into account expected morphine concentrations enables improved individualised decision making.

Property prediction and pharmacokinetic evaluation of mixed stoichiometry cocrystals of zafirlukast, a drug delivery case study

Cocrystals have been identified as a method for ensuring the delivery of poorly soluble drugs. Development of cocrystal phases presents many challenges, with the in vivo drug delivery benefits difficult to predict robustly. Additional to this, many of the benefits seen in the literature do not use formulation strategies which are representative of the clinical dosage form. Zafirlukast has been shown to possess poor development properties. It is poorly soluble and difficult to manufacture. Here we present a case study highlighting the benefits of cocrystals in this context, outlining the discovery, formulation and improved pharmacokinetics of mixed stoichiometry cocrystals of zafirlukast. This case study outlines methods, which could be broadly applied to other drug molecules, for determination of the properties of cocrystals through a suite of in vitro experiments that display a predictive pathway from physical form discovery to enhanced in vivo activity in animal models.

Rationalized Computer-Aided Design of Matrix-Metalloprotease-Selective Prodrugs

Matrix metalloproteinases (MMPs) are central to cancer development and metastasis. They are highly active in the tumor environment and absent or inactive in normal tissues; therefore they represent viable targets for cancer drug discovery. In this study we evaluated in silico docking to develop MMP-subtype-selective tumor-activated prodrugs. Proof of principle for this therapeutic approach was demonstrated in vitro against an aggressive human glioma model, with involvement of MMPs confirmed using pharmacological inhibition.