A comparative analysis of two different analysers used for determination of the Total Organic Carbon in pharmaceutical grade water

Total Organic Carbon (TOC) is a routine test for pharmaceutical grade water. Several manufacturers supply equipment of different designs but there is a dearth of published, peer-reviewed, information evaluating the various analysers. In this study, we compared two TOC analysers, both validated to the same pharmacopoeial criteria, but with different oxidation and detection methods. The results in this paper show that there were no unexplained out-of-specification results and that both analysers operated equivalently in terms of the pharmacopoeial 500ppb pass/fail limits. However, significant differences between the TOC levels reported from paired samples were observed, two paired samples recorded a pass/fail conflict (albeit flagged with an overestimation warning), as well as differences in analyser responses between spiked samples that contained low levels of nitro- and chloro-carbon compounds

Online UV imaging of API-excipient mixtures during dissolution

The Sirius SDI has been shown to provide real-time information of the dissolution process at the surface of drug compacts (1, 2). Here, the release mechanism of Carvedilol (CAR), a BCS class II drug, with either HPMC or Eudragit EPO was investigated

Comparative analysis of TOC and conductivity analysers as applied to pharmaceutical water analysis

Pharmaceutical grade water requires the measurement of bioburden, Total Organic Carbon and conductivity. Here we report a comparative analysis from two TOC analysers and two conductivity systems. The TOC analysers showed significantly different results

Solid oral dosage form manufacturing using injection moulding

The most preferred route of drug administration is via an oral dosage form and currently the most widely used manufacturing method is direct compression of powder blends. However it can be difficult to control the homogeneity of these dosage forms due to inefficient mixing. Dispersing API within a molten polymer can give more control over the spatial arrangement of drug within the dosage forms resulting in higher quality doses. Using polymers also has the added benefit that drug-polymer interactions can increase solubility of drugs reducing the growing concern of the number of aqueous insoluble drugs on the market (1). Injection Moulding (IM) is a novel method to produce dosage forms. It works by melting formulations containing polymer and drug together and injecting it into a cavity. By combining this technology with Hot Melt Extrusion (HME) which introduces highly efficient mixing the drug dose can be controlled. However the main disadvantage to using polymers is that sustained release often occurs due to the slow erosion properties and high pressures used during injection moulding(2). Stability issues can also occur when using high drug loadings as the polymer becomes saturated. Disintegrating agents can be introduced to the formulation in order to increase the time taken to obtain complete drug release. It is important to note that due to the nature or polymer true ‘disintegration’ won’t occur as it does with compressed tablets however they do have the ability to help facilitate the breakdown of polymers(3) . Filaments were produced using HME based on a Design of Experiments approach were analysed using disintegration apparatus and the results suggests the best disintegrating agents to use were small natural molecules. However the main factor influencing the mass remaining was the concentration of API as this was a BCS Class II drug. References 1. Karataş A, Yüksel N, Baykara T. 'Improved solubility and dissolution rate of piroxicam using gelucire 44/14 and labrasol'. Il Farmaco. 2005;60(9):777-82. 2. Claeys B, Vervaeck A, Hillewaere XKD, Possemiers S, Hansen L, De Beer T, et al. 'Thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding'. E. J. Pharm. Biopharm. 2015;90:44-52. 3. Agrawal A, Dudhedia M, Deng W, Shepard K, Zhong L, Povilaitis E, et al. 'Development of tablet formulation of amorphous solid dispersions prepared by hot melt extrusion using quality by design approach'. AAPS PharmSciTech. 2016;17(1):214-32

Manometric Temperature Measurement (MTM) lyophilisation of a challenging clinical trial pharmaceutical

INTRODUCTION Cancer Research UK Formulation Unit The Formulation Unit based at the University of Strathclyde in Glasgow has a research and development history in excess of 25 years, being funded by, and working in partnership with, firstly Cancer Research Campaign, and since 2002, with Cancer Research UK. The Unit is based in an entirely academic University setting, and since 2004 has been licensed by the UK government Medicines and Healthcare products Regulatory Agency (MHRA) for research, development and manufacture of Phase I/II novel small molecule cancer therapeutics and diagnostics. Research programs have delivered new formulations to clinical trial as either sterile or non-sterile presentations. However, the Unit’s specialty is based around small volume parenteral product manufacture. Boronophenylalanine (L-BPA) in Boron Neutron Capture Therapy (BNCT) L-BPA is the premier pharmaceutical selection in BNCT in treatment of selected head and neck tumours. BNCT relies on localisation of boron 10 within a tumour mass, made possible by the amino acid carrier portion of the L-BPA molecule. Phenylalanine is selectively transported across the blood brain barrier and then into astrocytic cells by a LAT-1 transporter system that is up-regulated in tumour. A targeted external neutron beam activates the accumulated L-BPA. In brief, neutron capture by boron causes nuclear re-arrangement and formation of a high linear energy transfer alpha particle and lithium 7 nuclei. Thus the patient is dosed with localised radiotherapy. OLD FORMULATION Issues existed with the previous standard formulation of L-BPA in fructose. L-BPA complexed with fructose has low solubility of around 30mg/mL. Consequently, large administration volumes are required to achieve clinical dosing in tens of grams of drug per patient. Moreover, L-BPA in fructose solutions must be freshly prepared and administered within 48 hours for reasons of product instability (Henriksson et al, 2008). Although rare, hereditary fructose intolerance needs to be considered. Taken together, L-BPA production, preparation and patient dosing is highly challenging. NEW FORMULATION Restrictions The Formulation Unit developed a new improved formulation; the drug product was a lyophilized pH8 solution of L-BPA at 100mg/mL in 110mg/mL mannitol (Schmidt et al, 2011). When lyophilised, a shelf life of 48 months was supported for the drug product. Whilst a three times increase in solubility, and a significantly enhanced product lifetime were worthy formulation enhancements, a new restriction emerged; the solution for lyophilisation contained 21% w/v solids far exceeding the ‘normal’ region of 2% w/v to 5% w/v (Boylan and Nail, 2009). Moreover, the lyophilisation cycle of 6 days was considered commercially unfavourable. A shortened drying cycle of 1 to 3 days would be preferred. Research was therefore initiated to reduce drying cycle time utilising Manometric Temperature Measurement (MTM) technology. MTM Studies MTM controlled freeze drying systems were originally marketed in the first decade of the new millennium. The ability to use software to calculate the performance at the freeze-drying front in real time is scientifically and commercially appealing. The possibility to optimize processing conditions at that same time as data is being received invites the prospect of a reduced experimentation phase thereby rapidly reaching the goal of a maximally efficient freeze drying cycle. In theory, even a minimally experienced operator could achieve this outcome. In summary, MTM functions by taking pressure rise information at regular intervals (Giesler et al, 2007). Based on SMART® software (SP Scientific, Stone Ridge, NY, USA), hourly pressure rise data are taken at a rate of 10 samples per second. The system calculates the product temperature at the sublimation interface and mass transfer resistance of the product. Adjustments are then automatically made to the shelf temperature and system pressure to achieve a calculated target product temperature. The end of primary drying can be determined by comparing the vapour pressure of ice with the system chamber pressure. Input data is minimal, such as vial number, inner vial area, fill volume and weight, concentration, product critical temperature. MATERIALS AND METHODS Chemicals Syntagon AB, Södertälje, Sweden manufactured BPA raw material according to EU current Good Manufacturing Practice (cGMP). D-mannitol (Ph. Eur) was sourced from Sigma-Aldrich, Poole, UK, and fuming hydrochloric acid and sodium hydroxide pellets (both extra pure Ph. Eur., BP, JP, NF) were obtained from VWR International, Lutterworth, UK. Water for Irrigation (WFI) in bulk was acquired from Baxter’s Healthcare Ltd., Norfolk, UK. Type 1 clear glass 50mL vials with 20mm butyl rubber stoppers (proved clean), crimped with 20mm tear off aluminium overseals were all from Adelphi Healthcare Packaging, Haywards Heath, UK. Lyophilisation equipment MTM software (SMART®) was operated on an FTS Systems Lyostar II drier (Biopharma, Winchester, UK). CONCLUSION A new improved L-BPA formulation in mannitol has been developed and used in human clinical trial. Further research using MTM technology succeeded in reducing a 6 day drug product drying cycle to 53 hours. The formulation exhibited non-ideal behaviour, and MTM failed to predict drying parameters, e.g., base of vial temperature, that are more closely replicated in ‘ideal’ test articles such as a 5% mannitol comparator. Further test lyophilisations are required to reach ideal. ACKNOWLEDGMENTS This research is funded by Cancer Research UK. REFERENCES 1. Boylan, J.C. and Nail, S.L. Parenteral Products, in: Florence, A.T. and Siepman, J. (Eds.), Modern Pharmaceutics. Informa Healthcare, New York, 565-609 (2009). 2. Giesler, H.; Kramer, T. and Pikal, M. J. Use of manometric temperature measurement (MTM) and SMART freeze dryer technology for development of an optimised freeze drying cycle. J. Pharm Sci. 96(12), 3402-3418 (2007). 3. Henriksson, R.; Capala, J.; Michanek, A.; Lindahl, S.A.; Satford, L.G.; Franzen, L.; Blomquist, E.; Westlin, J.E. and Bergenheim, A.T. Boron neutron capture therapy (BNCT) for glioblastoma multiforme: A phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA). Radiotherapy and Oncology 88, 183-191 (2008). 4. Schmidt, E.; Dooley, N.; Ford, S. J.; Elliott, M. and Halbert, G. W. Physicochemical investigation of the influence of saccharide based parenteral formulation excipients on L-p-boronphenylalanine solubilisation for Boron Neutron Capture Therapy. J. Pharm. Sci. 101(1), 223-232 (2011)

Characterisation of a liquid-capsule-fill-formulation performance on an automated capsule filling machine (CFS1000)

Automated manufacture of liquid filled hard gelatine capsules is dependant on the physical properties of a pharmaceutical formulation. Here, we investigated the performance of a novel formulation (phase I clinical trial) for automated capsule filling

Injection moulding : a novel approach to the manufacture of homogenous immediate release solid oral dosage forms

The current methods of dosage form production do not control the API spatial arrangement especially when using powder blends. This research aims to use Injection Moulding as a novel alternative method taking advantage of the benefits of drug-polymer interactions. Initial studies of paracetamol PVP formulations provided units that contained crystalline paracetamol due to inefficient mixing. Methods to produce solid dispersions prior to injecting such as Hot Melt Extrusions may be necessary