Search

The development of oral solid dosage forms, such as tablets that contain a high dose of drug(s), requires polymers and other additives to be incorporated at low levels as possible, to keep the final tablet weight low, and, correspondingly, the dosage form size small enough to be acceptable from a patient perspective. Additionally, a multi-step batch-based manufacturing process is usually required for production of solid dosage forms. This study presents the development and production, by twin-screw melt granulation technology, of a high-dose immediate-release fixed-dose combination (FDC) product of metformin hydrochloride (MET) and sitagliptin phosphate (SIT), with drug loads of 80% w/w and 6% w/w, respectively. For an 850/63 mg dose of MET/SIT, the final weight of the caplets was approximately 1063 mg compared with 1143 mg for the equivalent dose in Janumet®, the marketed product. Mixtures of the two drugs and polymers were melt-granulated at temperatures below the individual melting temperatures of MET and SIT (231.65 and 213.89°C, respectively) but above the glass transition temperature or melting temperature of the binder(s) used. By careful selection of binders, and processing conditions, direct compressed immediate-release caplets with desired product profiles were successfully produced. The melt granule formulations before compression showed good flow properties, were larger in particle size than individual starting API materials and were easily compressible. Melt granulation is a suitable platform for developing direct compressible high-dose immediate-release solid dosage forms of FDC products.

This work focused on the development of a concentric multi-layered fixed-dose combination via an advanced manufacturing technique, hot-melt co-extrusion. The dosage form was designed to offer differing release behaviour; immediate and sustained release from the coat and core, respectively. Hydrochlorothiazide and losartan potassium were incorporated as anti-hypertensive drugs. Solid-state characterisation revealed that both were transformed into their amorphous forms. In-vitro dissolution testing showed desired release performances offering both immediate and modified release.

Currently in the pharmaceutical industry, continuous manufacturing is an area of significant interest. In particular, hot-melt extrusion (HME) offers many advantages and has been shown to significantly reduce the number of processing steps relative to a conventional product manufacturing line. To control product quality during HME without process interruption, integration of inline analytical technology is critical. Vibrational spectroscopy (Raman, NIR and FT-IR) is often employed and used for real-time measurements because of the non-destructive and rapid nature of these analytical techniques. However, the establishment of reliable Process Analytical Technology (PAT) tools for HME of thermolabile drugs is challenging. Indeed, Raman effect is inherently weak and might be subject to interference such as scattering, absorption and fluorescence. Moreover, during HME, heating and photodecomposition can occur and disrupt spectra acquisition. The aim of this research article was to explore the use of inline Raman spectroscopy to characterise a thermolabile drug, ramipril (RMP), during continuous HME processing. Offline measurements by HPLC, LC-MS and Raman spectroscopy were used to characterise RMP and its main degradation product, ramipril-diketopiperazine (RMP-DKP, impurity K). A set of HME experiments together with inline Raman spectroscopic analysis were performed. The feasibility of implementing inline Raman spectroscopic analysis to quantify the level of RMP and RMP-DKP in the extrudate was addressed. Two regions in the Raman spectrum were selected to differentiate RMP and RMP-DKP. When regions were combined, a principle component analysis (PCA) model defined by these two main components (PC 1=50.1% and PC 2=45%) was established. Using HPLC analyses, we were able to confirm that the PC 1 score was attributed to the level of RMP-DKP, and the PC 2 score was related to the RMP drug content. Investigation of the PCA scatterplot indicated that HME processing temperature was not the only factor causing RMP degradation. Additionally, the plasticiser content, feeding speed and screw rotating speed can all contribute to the RMP degradation during HME processing.

The purpose of this work was to investigate the application of different advanced continuous processing techniques (hot melt extrusion and spray drying) to the production of fixed-dose combination (FDC) monolithic systems comprising of hydrochlorothiazide and ramipril for the treatment of hypertension. Identical FDC formulations were manufactured by the two different methods and were characterised using powder X-ray diffraction (PXRD) and modulated differential scanning calorimetry (mDSC). Drug dissolution rates were investigated using a Wood's apparatus, while physical stability was assessed on storage under controlled temperature and humidity conditions. Interestingly both drugs were transformed into their amorphous forms when spray dried, however, hydrochlorothiazide was determined, by PXRD, to be partially crystalline when hot melt extruded with either polymer carrier (Kollidon® VA 64 or Soluplus®). Hot melt extrusion was found to result in significant degradation of ramipril, however, this could be mitigated by the inclusion of the plasticizer, polyethylene glycol 3350, in the formulation and appropriate adjustment of processing temperature. The results of intrinsic dissolution rate studies showed that hot-melt extruded samples were found to release both drugs faster than identical formulations produced via spray drying. However, the differences were attributable to the surface roughness of the compressed discs in the Wood's apparatus, rather than solid state differences between samples. After a 60-day stability study spray dried samples exhibited a greater physical stability than the equivalent hot melt extruded samples.

Cranio-osteoarthropathy is a rare condition. Classically, signs are identifiable in infancy with clubbing of fingers, and delayed closure of the clinically enlarged cranial sutures, followed by periosteal new bone formation on X-rays of the long bones. Ultimately, joint swelling and stiffness follow, typically involving the large joints. We report two unrelated patients with features of cranio-osteoarthropathy, both of whom also had a history of congenital heart disease. Moreover, the cases reported here, manifesting significant differences in radiological features, emphasize the variability of radiological findings which can attend this condition.

Urinary tract infection (UTI) is one of the most common causes of unexplained fever in neonates. The aim of this study was to determine the incidence of urinary tract anomalies and acute renal damage in neonates who presented with first urinary tract infection in the first 8 weeks of life. We reviewed the records of 95 infants, who were hospitalised with UTI during a 6-year period (1994-1999). Patients with antenatally diagnosed hydronephrosis and incomplete radiological investigations were excluded from the study. Of the remaining 57 patients, 42 were boys and 15 girls. The mean age at diagnosis was 32 days (range 5-60 days). All patients underwent renal ultrasonography (US), voiding cystourethrogram (VCUG) and (99m)Tc-dimercaptosuccinic acid (DMSA) scan. Urinary tract abnormalities were detected in 20 (35%) patients. Vesicoureteral reflux (VUR) was found in 19 (33%) neonates, 7 girls and 12 boys. Acute cortical defects on DMSA scan were present in 19 kidneys of patients with VUR and in 25 of those without reflux. Only one-third of neonates after first symptomatic UTI had VUR. We recommend that US, VCUG, and DMSA scan should be routinely performed after the first UTI in infants younger than 8 weeks.

Donald Kirks justifies the appearance of another textbook of pediatric radiology on the grounds that a practical overview of pediatric imaging using all modalities is not currently available. I think he is correct and that this book will fill a void. The first chapter deals with the practical techniques of imaging in the pediatric patient. The concept of problem-oriented pediatric radiology is to the forefront. There are useful hints on equipment, protection, and special examinations. The subsequent seven chapters are divided by traditional organ systems and emphasize techniques of examination followed by excellent descriptions of common general abnormalities, including normal variants and rarer specific abnormalities. All chapters include excellent clear lists and diagrams, are profusely illustrated, and have excellent references. Finally, there are four appendices dealing with patient preparation, suggested projections, radiation dosage, and recommended techniques. Dr Kirks has directed this book at, among others, trainee radiologists, radiologists in general

It is always with great anticipation that one begins to review one of Leonard Swischuk's many publications. In this particular instance I had the added interest of having reviewed the previous, 1980, edition of this book, then titled Radiology of the Newborn and Young Infant . The change in title refleets much of what has changed in the practice of imaging diseases in the younger child. This book is presented in this textbook's traditional format divided into system-related chapters, eight in all. Within these chapters the material is presented in specific disease-related sections. Each of these sections ends with appropriate references. This juxtaposing of text and bibliography is an excellent method of integrating both items of information, but it does lead at times to the illustrations' lagging behind the text and gives rise to much turning of pages to find the appropriate figure. Some chapters stand out as being particularly good.

Some books understate their objectives, but most make relatively extravagant claims. Dr Swischuk, in the preface to this, the second edition of his book on plain film interpretation in congenital heart disease, states his objective to be "to provide a primer for the interpretation and understanding of the plain film roentgenographic findings in congenital heart disease." I think he is too modest. This is a fine comprehensive review of the subject and contains a large amount of useful information. There is a nice brief review of the relevant embryology of cardiovascular development that serves to make some of the more complex malformations a little more understandable. He divides the plain film findings in congenital heart disease according to the basic pulmonary vascular patterns. Though not a new approach, it makes for much easier classification for the student of congenital heart disease. Thus, discussion according to the patterns of increased pulmonary

These two volumes, originally published in French as part of the Traite de Radiodiagnostic by Masson, Paris, are now published in English with a translation by Dr Herbert J. Kaufmann. The contributing authors are all eminent French physicians, and the series was under the general direction of the late Jacques Lefebvre. Volume one, Heart and Great Vessels , begins with a chapter on methods of investigation and on radiologic anatomy. A useful and comprehensive section covers developmental anatomy and embryology. Congenital heart disease presenting mainly in the neonate, is dealt with in a separate chapter. There are descriptions of the radiology of left-to-right shunts, of abnormalities of the left side of the heart, and of malformations of the pulmonary vasculature. There is a section on anomalies of the aortic arch and assorted lesions, including the follow-up of operated lesions. The second volume, The Respiratory System , also begins with methods of investigation

Anatomy is for many medical people, this reviewer included, not the most exhilarating and inviting area of study. It was, therefore, with some trepidation that I approached the task of reviewing this atlas of anatomic illustrations, part of The Johns Hopkins Series in Contemporary Medicine and Public Health. Exceeding 450 pages of text and pictures, mainly line drawings, the atlas gives a detailed illustration of the anatomic features of the infant head and neck. Where relevant, comparisons are provided with the fetus and the adult, and when possible, the anatomy is related to functional performance, particularly in relation to the mouth, pharynx, and larynx. Further sections deal with detailed regional anatomy, both skeletal and soft tissue, including the ear, mouth, and upper airways. There is an interesting and most useful appendix on the dimensions of the human larynx during infancy and childhood and 24 tables of measurements. To my great

This, the second edition of Dr Swischuk's textbook of Radiology in the Newborn and Young Infant , appears seven years after the first and, while it contains most of the material first seen in 1973, it has been changed and expanded to reflect the vast explosion in medical knowledge and imaging techniques since that time. This edition contains many new illustrations, and several sections have been greatly expanded, including those on hyaline membrane disease, necrotising enterocolitis, ureteric reflux, and intracranial hemorrhage. Of the nine chapters, those on the respiratory system and the alimentary tract are the largest, occupying almost 200 pages each. There are approximately 100 pages devoted to the cardiovascular system, genitourinary tract, skeleton, and cranium, with shorter sections on the upper airway and the spine. Finally, there is a short but useful chapter on fetal and perinatal radiology. The exceptionally extensive bibliography is up to date, with references from

Seven years after the appearance of Gastrointestinal Radiology in Pediatrics , Dr Franken has delivered the second edition. The new title, Gastrointestinal Imaging in Pediatrics , reflects both the changing practice of the radiologist and the expanded content of this textbook. This edition has 632 pages, compared with a previous 323. The list of authors has suffered even higher inflation—from two to 18, drawn from three continents. The price is a modest $75. The first chapter deals with techniques of examination and will be very helpful to those who examine children infrequently. Chapters 2 to 11 give a systematic account of the radiology of the gastrointestinal (GI) tract, including liver, pancreas, and spleen. There are separate and extensive chapters on angiography, computed tomography, nuclear medicine, and ultrasound. Each chapter concludes with an extensive list of references. This is a good textbook. It is a comprehensive text by leading experts in each field.