Continuous direct compression
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The transfer from batch-based to continuous tablet manufacturing increases the quality and efficiency of processes. Nonetheless, as in the development of a batch process, the continuous process design requires optimization studies to ensure a robust process. In this study, processing of a commercially batch-manufactured tablet product was tested with two continuous direct compression lines while keeping the original formulation composition and tablet quality requirements. Tableting runs were conducted with different values of process parameters. Changes in parameter settings were found to cause differences in tablet properties. Most of these quality properties could be controlled and maintained within the set limits effortlessly already at this stage of studies. However, the API content and content uniformity seemed to require more investigation. The observed content uniformity challenges were traced to individual tablets with a high amount of API. This was suspected to be caused by API micro-agglomerates since tablet weight variability did not explain the issue. This could be solved by adding a mill between two blenders in the process line. Overall, this case study produced promising results with both tested manufacturing lines since many tablet properties complied with the test result limits without optimization of process parameter settings.
Continuous tablet manufacturing is a competitive option to replace the traditional batch manufacturing approach. The aim of this study was to evaluate technology transfer from batch-based direct compression of a commercial tablet formulation to continuous direct compression without changes to the composition of the formulation. Some powder studies were conducted with the raw materials and multi-tip punches were utilized in the tableting studies. To lower the high level of tablet weight variability that was evident during preliminary tests, a process parameter optimization was performed using an experimental design with different rpm values of force feeder and mixer impeller. By selecting the most appropriate settings of these parameters for the studied product, the weights of the tablets could be controlled adequately to meet the specification criteria. The functionality of the best-performing parameter settings was investigated with a three-hour-long tableting run. The tablets were evaluated with the same quality criteria as the commercial batch-produced tablets, and they passed all the tests performed in this study. Despite the challenging material properties according to the flowability tests, production of tablets with the desired quality was achieved using the original composition with continuous direct compression.
- MeSH
- bisoprolol * MeSH
- farmaceutická technologie * MeSH
- prášky, zásypy, pudry MeSH
- příprava léků MeSH
- tablety MeSH
- tlak MeSH
- Publikační typ
- časopisecké články MeSH
Transferring an existing marketed pharmaceutical product from batch to continuous manufacturing (CM) without changes in regulatory registration is a challenging task in the pharmaceutical industry. Continuous manufacturing can provide an increased production rate and better equipment utilisation while retaining key quality attributes of the final product. Continuous manufacturing necessitates the monitoring of critical quality attributes in real time by appropriate process analytical tools such as near infra-red (NIR) probes. The present work reports a successful transfer of an existing drug product from batch to continuous manufacturing process without changing the formulation. A key step was continuous powder blending, whose design and operating parameters including weir type, agitation rate, dynamic hold-up and residence time were systematically investigated with respect to process repeatability. A NIR-based multivariate data model for in-line composition monitoring has been developed and validated against an existing quality control method for measuring tablet content uniformity. A continuous manufacturing long-run with a throughput of 30 kg/h (approx. 128,000 tablets per hour), uninterrupted for 320 min, has been performed to test and validate the multivariate data model as well as the batch to continuous process transfer. The final disintegration and dissolution properties of tablets manufactured by the continuous process were found to be equivalent to those manufactured by the original batch process.
- MeSH
- blízká infračervená spektroskopie metody MeSH
- farmaceutická chemie metody MeSH
- farmaceutická technologie * metody MeSH
- pomocné látky chemie MeSH
- prášky, zásypy, pudry chemie MeSH
- příprava léků metody MeSH
- řízení kvality MeSH
- rozpustnost MeSH
- tablety * MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články MeSH
Cíl. Ověřit přesnost metody "tlakového provokačního testu" v ultrazvukové diagnostice intrakraniální hypertenze u novorozenců s diagnózou posthemoragického hydrocefalu (PHH). Hlavním cílem bylo ověřit, zda klidový nebo kompresní index rezistence koreluje s přítomností intrakraniální hypertenze. Vedlejším cílem bylo zjištění závislosti mezi stupněm nitrolební hypertenze a velikostí komor, posouzení rychlosti rozvoje PHH a zjištění, ve kterém období se vyskytuje nejčastěji. Metoda. Vyšetřovaný soubor zahrnuje 52 dětí s diagnózou posthemoragického hydrocefalu (PHH), které byly vyšetřeny na našem pracovišti v letech 1999-2008. Průměrná porodní hmotnost dětí s PHH byla 1436 g v rozmezí 550-4090 g, medián 1150 g. Gestační stáří bylo 29,6 týdne (24.-41. týden), medián 28. týden. Celkem bylo v souboru 73 % dětí s velmi nízkou porodní hmotností (VLBW). Z celkového počtu 445 měření bylo ke statistickému zpracování vybráno 162 hodnot. Kritériem výběru bylo současné změření velikosti komor, klidového indexu rezistence (IR), indexu rezistence po stlačení velké fontanely (IRc) a zjištění intrakraniálního tlaku přímou metodou (ICPm). Výsledky. Posthemoragický hydrocefalus se vyvinul průměrně za 16 dnů po porodu, do 19. dne po porodu jsme prokázali intrakraniální hypertenzi u 95 % dětí. Z celkového počtu měření IRc (n = 162) jsme měli sedm falešně negativních a čtyři falešně pozitivní výsledky, při ICPm > 11 cm jsme měli jeden falešně negativní výsledek. Hodnoty IR u dětí s prokázanou intrakraniální hypertenzí byly v 71,3 % (107 měření) falešně negativní a nekorelovaly s hodnotou ICP (p > 0,5). Velikost komor neměla vztah k zjištěné hodnotě ICPm. Celková přesnost metody dosáhla 93,2 % při senzitivitě (95,5 %) a nízké specificitě (36,4 %). Závěr. Kompresní dopplerovská ultrasonografie dokáže s vysokou přesností stanovit přítomnost nitrolební hypertenze ještě před rozvojem klinických příznaků.
Aim. We wanted to try and verify the method of "pressure provocation test". The primary objective was to verify, if the basic and compressive resistive index correlates with the presence and eventually with the severity of intracranial hypertension. The secondary objective was to find relationship between the degree of intracranial hypertension and the diameter of cerebral ventricles, to asses the rapidity of PHH developement and to find out, in which period is PHH the most common. Method. In years 1999-2008, 52 children with diagnosis of posthemorrhagic hydrocephalus were examined in our department. The average birth weight in children with PHH was 1436 g (550-4090 g, median 1150 g). The average age was 29,6 weeks (24-41 weeks, median 28 weeks). Totally, 73% of children had very low birth weight (VLBW). From the total count of 445 examinations, 162 values were chosen for the next statistic processing. The criterium for choice was simultaneous measurement of ventricle diameters, basic resistive index (IR), compressive resistive index (IRc) and direct intracranial pressure measurement (ICPm). Results. Posthemorrhagic hydrocephalus developed on average in 16 days after the childbirth, till day 19 after the birth intracranial hypertension was proved in 95% of children. From the total count of measurements (n = 162), IRc were false negative (7) and false positive (5), in ICPm > 11 cm there was one false negative outcome. The IR values in children with proved intracranial hypertension were in 71.3% (107 measurements) false negative and didn?t correlate to the value of ICP (p < 0.5). There was no correlation found between the ventricle diameter and the measured value of ICPm. The total accuracy of the method achieved 93.2% with high sensitivity (95.5%) and low specificity (36.4%). Conclusion. Compressive doppler ultrasonography is able with high accuracy to determine the presence of intracranial hypertension even before development of clinical signs.
- MeSH
- dopplerovská echokardiografie metody využití MeSH
- hydrocefalus diagnóza etiologie MeSH
- intrakraniální hypertenze diagnóza etiologie MeSH
- intrakraniální krvácení etiologie komplikace MeSH
- kohortové studie MeSH
- kojenec MeSH
- lidé MeSH
- mozkové komory ultrasonografie MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
A palsy of the brachial plexus elements caused by carrying a heavy backpack is a very rare injury usually occurring in soldiers or hikers, and recovery is usually spontaneous. We describe here the case of male civilian presenting with an isolated serious axillary nerve palsy associated with chronic backpack use. During the surgery, a dumbbell-shaped neuroma-in-continuity was found which was caused by direct pressure from the subscapular artery. After resection of the neuroma, a nerve graft from the sural nerve was used to reconstruct the nerve. Reinnervation was successful and the patient was able to abduct his arm to its full range, with full muscle strength, within 24 months.
- MeSH
- arterie zranění MeSH
- dospělí MeSH
- elektromyografie MeSH
- elektrostimulační terapie MeSH
- lidé MeSH
- nervus suralis transplantace MeSH
- neurochirurgické výkony metody MeSH
- neurologické vyšetření MeSH
- neurom chirurgie MeSH
- poranění periferního nervu etiologie patofyziologie chirurgie MeSH
- regenerace nervu MeSH
- rozsah kloubních pohybů MeSH
- svalová síla fyziologie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
As is the case with batch-based tableting processes, continuous tablet manufacturing can be conducted by direct compression or with a granulation step such as dry or wet granulation included in the production procedure. In this work, continuous manufacturing tests were performed with a commercial tablet formulation, while maintaining its original material composition. Challenges were encountered with the feeding performance of the API during initial tests which required designing different powder pre-blend compositions. After the pre-blend optimization phase, granules were prepared with a roller compactor. Tableting was conducted with the granules and an additional brief continuous direct compression run was completed with some ungranulated mixture. The tablets were assessed with off-line tests, applying the quality requirements demanded for the batch-manufactured product. Chemical maps were obtained by Raman mapping and elemental maps by scanning electron microscopy with energy-dispersive X-ray spectroscopy. Large variations in both tablet weights and breaking forces were observed in all tested samples, resulting in significant quality complications. It was suspected that the API tended to adhere to the process equipment, accounting for the low API content in the powder mixture and tablets. These results suggest that this API or the tablet composition was unsuitable for manufacturing in a continuous line; further testing could be continued with different materials and changes in the process.
In trauma patients, pulmonary embolism occurs in up to 4% of cases and carries a mortality of 20-50%. The incidence of deep vein thrombosis (DVT) varies from 5 to 63% depending on patients' risk factors, modality of prophylaxis, and methods of detection. For these reasons, trauma patients require adequate DVT prophylaxis. RECENT FINDINGS: Spinal fracture or cord injury patients are at particular risk. Increasing injury severity, head injury, older age, lower limb injuries, and obesity are other risk factors. The current standard of care for DVT prophylaxis is enoxaparin (a low molecular weight heparin) as long as anticoagulation is not contraindicated. Unfractionated heparin alone does not provide sufficient protection against DVT. Selective factor Xa inhibitors such as fondaparinux are showing promising results. Other strategies for pulmonary embolism prevention include: graduated compression stockings, sequential compression devices, continuous passive motion, and prophylactic inferior vena cava filter. There is lack of consensus regarding the optimal DVT prophylaxis in trauma patients and few level I recommendations exist. SUMMARY: Best practice in thromboprophylaxis for trauma patients will remain on the basis of recommendations until definitive risk-benefit ratios are determined to justify the use of various mechanical and pharmacological measures, in combination or alone.
- MeSH
- antikoagulancia terapeutické užití MeSH
- časové faktory MeSH
- enoxaparin terapeutické užití MeSH
- faktor Xa MeSH
- incidence MeSH
- inhibitory faktoru Xa MeSH
- kritický stav MeSH
- lidé MeSH
- plicní embolie epidemiologie etiologie prevence a kontrola MeSH
- polysacharidy terapeutické užití MeSH
- rány a poranění komplikace MeSH
- rizikové faktory MeSH
- žilní trombóza epidemiologie etiologie prevence a kontrola MeSH
- Check Tag
- lidé MeSH
Práce je zaměřena na výrobu hypromelosových gelových matric lisováním granulátu předem připraveného termoplastickou granulací. Modelovým léčivem byl theofylin monohydrát. Jako tající pojivo se použil montanglykolový vosk v koncentraci 10 a 20 %. Z dosažených výsledků vyplývá, že proces termoplastické granulace zajišťuje vznik granulátu s vhodnou pórovitostí, tokovými vlastnosti a velikostí částic. V obou disolučních médiích (fosforečnanovém pufru pH 6,8 a umělé žaludeční šťávě pH 1,2) závisí uvolňování modelového léčiva na použitém viskozitním stupni hypromelosy (HPMC). Uvolňování theofylinu lze řídit také změnou vzájemného poměru HPMC K a montanglykolového vosku. Pokles vzájemného poměru se projeví zvýšením rychlosti liberace léčiva. Vzhledem k rozdílné rozpustnosti léčiva ve zvolených disolučních médiích se theofylin významně rychleji uvolňuje ve fosforečnanovém pufru pH 6,8 než v umělé žaludeční šťávě pH 1,2. Matrice stejného složení se připravily také přímým lisováním. Ze vzájemného srovnání disolučních profilů vzorků připravených různými výrobními postupy plyne, že použitá metoda přípravy nemá vliv na uvolňování léčiva z matrice.
The paper focuses on the formulation of HPMC K-matrix tablets by compression of granulates previously prepared by melt granulation. The model drug was theophylline monohydrate. Montanglycol wax was used as the solid lipid binder in a concentration of 10-20 %. With respect to the obtained results, thermoplastic granulation was found to ensure suitable porosity, flow, and particle size of the granulates. In both dissolution media (phosphate buffer pH 6.8 and artificial gastric juice pH 1.2), the release of the model drug is dependent on the HPMC viscosity grade used. The release rate can be modified by a change in the HPMC-to-montanglycol wax ratio. A decrease in this ratio increases the liberation of theophylline monohydrate. Due to different drug solubilities in the selected dissolution media, theophylline is released significantly faster in phosphate buffer pH 6.8 then in artificial gastric juice pH 1.2. The matrices of the same composition were prepared by direct compression; the comparison of dissolution profiles shows that the release of the active substance is not influenced by the employed method of manufacture.
PURPOSE OF THE STUDY The aim of this retrospective study was to evaluate the results of intra-operative myelography as the method used to assess the reduction of bone fragments from the posterior margin of the vertebral body. MATERIAL AND METHODS Forty patients with 42 comminuted fractures of the thoracolumbar spine were included in the study. The pre-operative spinal stenosis caused by bone fragments from the posterior margin of the vertebral body, as detected by CT scanning, ranged from 25 % to 85 %. Neurological deficit was due to injury in 19 patients and in one it developed post-operatively after the patient stood and walked. After ligamentotaxis and internal fixation, intra-operative myelography was used to show decompression of the spinal canal. A spinal block or severe constriction of contrast flow was an indication for hemilaminectomy (laminectomy) and direct decompression of the spinal canal. In the patients with neurological deficit and severe spinal stenosis persisting after ligamentotaxis and detectable by skiascopy, hemilaminectomy (laminectomy) and direct spinal decompression followed by intra-operative myelography were carried out. RESULTS Intra-operative myelography was used 46 -times (20-times in 20 patients free from neurological deficit and 26-times in 20 patients with neurological deficit). In 38 cases (82.6 %) dural sac compression was not present (patients with neurological deficit, 13-times after ligamentotaxis, eight-times after ligamentotaxis and hemilaminectomy with direct decompression, twice at repeat surgeryúúú patients without neurological deficit, 15-times). On two occasions (4.4 %) the contrast agent injected into the dural sac did not make the interior body part visible, on three occasions (6.5 %) contrast medium was injected extradurally, and dural sac compression following ligamentotaxis requiring hemilaminectomy (laminectomy) and direct decompression occurred in three cases (6.5 %). In the patients without neurological deficit, dural sac compression was not recorded. No serious complications associated with contrast medium injection in the dural sac were present, and there was no deterioration of neurological symptoms due to a dural tap. In three cases (6.5 %) a false negative finding was recorded, showing free flow of contrast medium with no areas of constriction or obstruction and signs of post-operative nerve irritation (radicular syndrome associated with L3 fracture with a fragment placed laterally in two patients and hyperalgesia of the thigh after T12 fracture in one patient). Repeat surgery and additional decompression (hemilaminectomy and foraminotomy, laminectomy) resulted in immediate resolution of neurological symptoms. DISCUSSION The success rate, complications and disadvantages of intra-operative myelography have not been reported. At present, ionic water-soluble contrast agents used for intrathecal administration are associated with only a low number of serious complications. Neurological deficit due to dural tap is rare. Extradural administration is not effective. A disadvantage reported here involves a failure to visualize the area because of a low amount of contrast agent administered to avoid spinal cord injury. A possibility of false negative findings arising from only one lateral view of the contrast agent flowing round fragments is the major disadvantage. In contrast to the previous reports, we relate the false negative findings to neurological findings. CONCLUSIONS Intra-operative myelography is still a currently used method. Its advantages include a simple procedure without removal of posterior column structures, and the possibility of objective recording and continuous observation of the dural sac. The free flow of contrast medium makes obstruction of the spinal canal impossible. The consequences of a false negative finding can be successfully treated at the second stage.
- MeSH
- bederní obratle chirurgie radiografie zranění MeSH
- dospělí MeSH
- fraktury páteře chirurgie radiografie MeSH
- hrudní obratle chirurgie radiografie zranění MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- myelografie MeSH
- peroperační doba MeSH
- senioři MeSH
- tříštivé fraktury chirurgie radiografie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- senioři MeSH
Nowadays, most of the newly developed active pharmaceutical ingredients (APIs) consist of cohesive particles with a mean particle size of <100μm, a wide particle size distribution (PSD) and a tendency to agglomerate, therefore they are difficult to handle in continuous manufacturing (CM) lines. The current paper focuses on the impact of various glidants on the bulk properties of difficult-to-handle APIs. Three challenging powders were included: two extremely cohesive APIs (acetaminophen micronized (APAPμ) and metoprolol tartrate (MPT)) which previously have shown processing issues during different stages of the continuous direct compression (CDC)-line and a spray dried placebo (SD) powder containing hydroxypropylmethyl cellulose (HPMC), known for its sub-optimal flow with a high specific surface area (SSA) and low density. Four flow-enhancing excipients were used: a hydrophilic (Aerosil® 200) and hydrophobic (Aerosil® R972) fumed silica grade, a mesoporous silica grade (Syloid® 244FP), and a calcium phosphate excipient (TRI-CAFOS® 200-7). The APIs and binary API/glidant blends (varied between 0.5-2.75 w/w%) were characterized for their bulk properties relevant for CDC. The results indicated that optimizing different bulk parameters (e.g., density, flow, compressibility..) of an API required varying weight percentages of the glidant (e.g., different surface area coverage (SAC)) depending on the APIs. Moreover, even at similar SAC, the impact of the glidant on the bulk characteristic of the APIs depended on the glidant type properties. While nano-sized silicon dioxide were effective for improving the flowability of a powder, other glidants (mesoporous silica and tricalcium phosphate (TCP)) showed also promise as alternatives. Additionally, an excess of glidant, referred to as oversilication, negatively impacted some bulk parameters, but other characteristics were unaffected. Finally, to determine the appropriate concentration of the different classes of glidants, SAC calculations, an understanding of the glidant's working mechanism, and knowledge about the API's characteristics (i.e., morphology, compressibility, flowability, aeration, density, and wall friction) are required. This study confirmed the necessity of including various material characterization techniques to assess the impact of glidants on the bulk characteristics of APIs.
- MeSH
- deriváty hypromelózy * chemie MeSH
- farmaceutická chemie metody MeSH
- fosforečnany vápenaté * chemie MeSH
- hydrofobní a hydrofilní interakce MeSH
- metoprolol * chemie MeSH
- nerozplněné léky MeSH
- oxid křemičitý chemie MeSH
- paracetamol * chemie MeSH
- pomocné látky * chemie MeSH
- prášky, zásypy, pudry * MeSH
- příprava léků metody MeSH
- reologie * MeSH
- velikost částic * MeSH
- Publikační typ
- časopisecké články MeSH
