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Bergstrom C.A.S.,Uppsala University | Holm R.,Lundbeck | Jorgensen So.A.,Copenhagen University | Andersson S.B.E.,Uppsala University | And 14 more authors.
European Journal of Pharmaceutical Sciences | Year: 2014

Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silico and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered. © 2013 Elsevier B.V. All rights reserved.


PubMed | Pfizer, Sirius Analytical Instruments Ltd. and University of Bath
Type: | Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences | Year: 2016

The pharmaceutical development of new chemical entities can be hampered by their solubility and/or dissolution limitations. Currently, these properties are characterised mostly during in vivo pre-clinical studies. The development of appropriate in vitro methods to study the solubility and dissolution properties in preclinical species would lead to a significant reduction or replacement of the animal experiments at this stage of development. During clinical development, media simulating the human gastrointestinal tract fluids are commonly used and a similar approach mimicking laboratory animals gastrointestinal tract fluids would impact on the preclinical stage of development. This review summarises the current knowledge regarding the gastrointestinal physiology of the most common laboratory animals, and animal simulated gastric and intestinal media are proposed.


PubMed | Johnson & Johnson, Copenhagen University, Pfizer, University of Strathclyde and 8 more.
Type: | Journal: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences | Year: 2014

Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silico and in vitro models typically used to forecast active pharmaceutical ingredients (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered.


Volgyi G.,Semmelweis University | Baka E.,Semmelweis University | Box K.J.,Sirius Analytical Instruments Ltd. | Comer J.E.A.,Sirius Analytical Instruments Ltd. | Takacs-Novak K.,Semmelweis University
Analytica Chimica Acta | Year: 2010

In this paper the pH-equilibrium solubility profiles of six organic drugs are presented. The equilibrium solubility values were determined using the saturation shake-flask and the Chasing Equilibrium Solubility (CheqSol) methods. Results obtained by the two methods are in good agreement. The aim of the present work was to study the validity of the Henderson-Hasselbalch (HH) relationship in the case of structurally diverse weak bases. The significance of pH control and the effect of the salt form (e.g., fumarate) was also investigated. In the case of monoprotic bases, namely papaverine, promethazine, propafenone and ticlopidine the experimental solubility data precisely follow the HH equation until the limit of salt solubility. The common ion effect on salt solubility was found to be significant at low pHs. Deviation from the HH equation in the case of dibasic quetiapine hydrogen fumarate and the ampholyte desvenlafaxine hydrogen fumarate can be easily interpreted with the formation of different salt compositions. It was concluded that precise pH control is essential in shake-flask solubility measurements. It is also critical that the pKa value and the intrinsic solubility are accurately determined when the HH relationship is used to predict the pH-dependent aqueous solubility of drugs. © 2010 Elsevier B.V.


Gravestock T.,Sirius Analytical Instruments Ltd. | Box K.,Sirius Analytical Instruments Ltd. | Comer J.,Sirius Analytical Instruments Ltd. | Frake E.,Sirius Analytical Instruments Ltd. | And 2 more authors.
Analytical Methods | Year: 2011

This paper describes a low volume, in vitro apparatus for investigating the dissolution and precipitation behaviour of active pharmaceutical ingredients (APIs) under a wide range of experimental conditions and dissolution media. The apparatus has automated and dynamic pH control, allowing the simulated passage of drugs through the gastrointestinal tract (GIT). Experiments can be performed in the presence of biorelevant media and excipients, providing information related to the predicted behaviour of APIs under physiological conditions. The technique is described in detail and results are presented for a number of neutral, basic, acidic and ampholytic drug compounds. © 2011 The Royal Society of Chemistry.


Indulkar A.S.,Purdue University | Box K.J.,Sirius Analytical Instruments Ltd. | Taylor R.,Sirius Analytical Instruments Ltd. | Ruiz R.,Sirius Analytical Instruments Ltd. | Taylor L.S.,Purdue University
Molecular Pharmaceutics | Year: 2015

Supersaturated solutions of poorly aqueous soluble drugs can be formed both in vivo and in vitro. For example, increases in pH during gastrointestinal transit can decrease the aqueous solubility of weakly basic drugs resulting in supersaturation, in particular when exiting the acidic stomach environment. Recently, it has been observed that highly supersaturated solutions of drugs with low aqueous solubility can undergo liquid-liquid phase separation (LLPS) prior to crystallization, forming a turbid solution such that the concentration of the drug in the continuous solution phase corresponds to the amorphous solubility while the colloidal phase is composed of a disordered drug-rich phase. Although it is well established that the equilibrium solubility of crystalline weakly basic drugs follows the Henderson-Hasselbalch relationship, the impact of pH on the LLPS phenomenon or the amorphous solubility has not been explored. In this work, the LLPS concentration of three weakly basic compounds - clotrimazole, nicardipine, and atazanavir - was determined as a function of pH using three different methods and was compared to the predicted amorphous solubility, which was calculated from the pH-dependent crystalline solubility and by estimating the free energy difference between the amorphous and crystalline forms. It was observed that, similar to crystalline solubility, the experimental amorphous solubility at any pH follows the Henderson-Hasselbalch relation and can be predicted if the amorphous solubility of the free base is known. Excellent agreement between the LLPS concentration and the predicted amorphous solubility was observed. Dissolution studies of amorphous drugs showed that the solution concentration can reach the corresponding LLPS concentration at that pH. Solid-state analysis of the precipitated material confirmed the amorphous nature. This work provides insight into the pH-dependent precipitation behavior of poorly water-soluble compounds and provides a fundamental basis with which to understand the performance of supersaturating dosage forms. (Graph Presented). © 2015 American Chemical Society.


Grant
Agency: GTR | Branch: Innovate UK | Program: | Phase: Smart - Development of Prototype | Award Amount: 185.18K | Year: 2013

We want to build an instrument to simulate what happens at the site of injection when a drug is administered subcutaneously into the human body. The instrument will be used to test newformulations, and to control the quality of manufactured batches of existing products. Many new drugs are biopharmaceuticals, such as proteins or peptides. Due to poor stability and absorption via the oral route, they can’t be taken by mouth, and the most practical way to administer them is by injection just under the skin. This method of delivery is called subcutaneous injection. Biopharmaceuticals delivered as subcutaneous injections are usually formulated as solutions containing buffers and other ingredients to improve patient comfort and product shelf-life. However, at present, the scientists involved in developing these products do not have access to a laboratory model that would allow estimating the effect of the formulation components on the bioavailability and rate of absorption of the drug from these formulations. Animal tests are used for this purpose instead, but are unpopular and don’t represent humans well. Tests with humans on the other hand are risky and expensive. To address the lack of a suitable laboratory model for subcutaneous injection, scientists at the University of Bath have developed a basic prototype of the instrument. They’ve asked Sirius Analytical Instruments Ltd., an established UK-based manufacturer to turn their idea into a robust, reliable product. Market research undertaken by Sirius Analytical, during which leading biopharmaceutical scientists were interviewed in depth, indicates a strong desire for this instrument spread over pharmaceutical and biotech companies in several countries. No other company is working in this area; it will be a unique product. The code name of the instrument is “ScISSOR” (Subcutaneous Injection Site SimulatOR). ScISSOR will be developed and manufactured in the UK. We estimate that 80% of production will be exported.


Grant
Agency: GTR | Branch: Innovate UK | Program: | Phase: Smart - Development of Prototype | Award Amount: 218.13K | Year: 2013

Our goal is to build a new instrument that can be used by pharmaceutical scientists to investigate formulations of “small molecule” drugs. The active pharmaceutical ingredients (APIs) in most drugs on the market today are organic compounds with molecular weight of 500 or less which interact with receptors in the human body to produce a desired therapeutic effect. Only a few milligrams of these APIs are required for a single dose. On their own, these doses would look like a few specks of white powder, so they must be mixed with inert ingredients called excipients to create tablets or capsules which are of a manageable size for the patient. As well as providing bulk, formulations are used to modify the behaviour of APIs. Two common procedures are to control the release of API in order to prolong the effect of the drug over a long period, and to enhance the solubility of poorly soluble APIs to improve their bioavailability. Controlled release can be investigated by dissolution experiments, and solubility enhancement is often achieved by taking advantage of supersaturation. We have developed a new technique for investigating dissolution under changing pH conditions and in the presence of a lipid phase to mimic the GI tract. We also hold a patent on a technique for measuring solubility and supersaturation. We have demonstrated the value of these techniques to customers of our analytical service. We now seek to develop an automated instrument that we will design specifically for formulation scientists to exploit this newly developed technology. Modifying the behaviour of APIs requires clever chemistry. In the past, new compounds were often shelved because of poor solubility, but recent efforts of formulation scientists have managed to make some extremely poorly soluble APIs into successful drugs. Formulation is an important aspect of drug development. All large pharmaceutical companies have formulation departments, as do generics manufacturers and many subcontractors.


Grant
Agency: GTR | Branch: Innovate UK | Program: | Phase: Feasibility Study | Award Amount: 208.56K | Year: 2015

Tens of thousands of animals are sacrificed every year in the UK during drug toxicity testing; many more worldwide. Toxicity testing is an important part of drug development. Newly discovered molecules are tested, as well as metabolites and new formulations. The tests are generally done on rats, mice and dogs. Many of these tests are not actually done to test toxicity, but in preliminary studies to gather data used to design the final toxicity study. This preliminary data data is used to design fit-for-purpose formulations, mainly for orally-administered drugs. We believe that most preliminary experiments using animals could be replaced by in-vitro tests. In this project, Pfizer will supply data from completed toxicological studies. Sirius will re-create the formulations and run in-vitro experiments to assess physicochemical characteristics and bioavailability. Scientists at the University of Bath will analyse the in-vitro data and look for IVIVC (in-vitro/in-vivo correlation). If the project is able to demonstrate that fit-for-purpose formulations can be assessed using in-vitro experiments, some 50% of animal experiments for testing drug toxicity could be eliminated.

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