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.
- Klíčová slova
- Blending, Pharmaceutical continuous manufacturing, Process parameters, Tablet compaction, Twin screw feeding,
- MeSH
- farmaceutická chemie * metody MeSH
- farmaceutická technologie metody MeSH
- pomocné látky * chemie MeSH
- příprava léků * metody MeSH
- tablety * 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.
- Klíčová slova
- Continuous manufacturing, Continuous powder blending, Direct compression, Near-infrared probe, Residence time,
- 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
- Názvy látek
- pomocné látky MeSH
- prášky, zásypy, pudry MeSH
- tablety * 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.
- Klíčová slova
- Dry granulation, Oral solid dosage form, Pharmaceutical continuous manufacturing, Tableting, Twin screw feeding,
- MeSH
- atorvastatin MeSH
- farmaceutická technologie * metody MeSH
- prášky, zásypy, pudry chemie MeSH
- příprava léků metody MeSH
- tablety chemie MeSH
- tlak MeSH
- velikost částic MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- atorvastatin MeSH
- prášky, zásypy, pudry MeSH
- tablety MeSH
Milling affects not only particle size distributions but also other important granule quality attributes, such as API content and porosity, which can have a significant impact on the quality of the final drug form. The ability to understand and predict the effects of milling conditions on these attributes is crucial. A hybrid population balance model (PBM) was developed to model the Comil, which was validated using experimental results with an R2 of above 0.9. This presented model is dependent on the process conditions, material properties and equipment geometry, such as the classification screen size. In order to incorporate the effects of different quality attributes in the model physics, the dimensionality of the PBM was increased to account for changes in API content and porosity, which also produced predictions for these attributes in the results. Additionally, a breakage mode probability kernel was used to introduce dynamic breakage modes by predicting the probability of attrition and impact mode, which are dependent on the process conditions and feed properties at each timestep.
- Klíčová slova
- Milling, breakage mode, granule quality attributes, population balance model,
- MeSH
- farmaceutická technologie * metody MeSH
- poréznost MeSH
- příprava léků metody MeSH
- velikost částic MeSH
- Publikační typ
- časopisecké články MeSH
Due to the possibility of designing various spatial structures, three-dimensional printing can be implemented in the production of customized medicines. Nevertheless, the use of these methods for the production of dosage forms requires further optimization, understanding, and development of printouts' quality verification mechanisms. Therefore, the goal of our work was the preparation and advanced characterization of 3D printed orodispersible tablets (ODTs) containing fluconazole, printed by the fused deposition modeling (FDM) method. We prepared and analyzed 7 printable filaments containing from 10% to 70% fluconazole, used as model API. Obtaining a FDM-printable filament with such a high API content makes our work unique. In addition, we confirmed the 12-month stability of the formulation, which, to our knowledge, is the first study of this type. Next, we printed 10 series of porous tablets containing 50 mg of API from both fresh and stored filaments containing 20 %, 40 %, or 70 % fluconazole. We confirmed the high quality and precision of the printouts using scanning electron microscopy. The detailed analysis of the tablets' disintegration process included the Pharmacopeial test, but also the surface dissolution imaging analysis (SDI) and the test simulating oral conditions performed in own-constructed apparatus. For each composition, we obtained tablets disintegrating in less than 3 min, i.e., meeting the criteria for ODTs required by the European Pharmacopeia. The filaments' storage at ambient conditions did not affect the quality of the tablets. All printed tablets released over 95% of the fluconazole within 30 min. Moreover, the printouts were stable for two weeks.
- Klíčová slova
- Fused deposition modeling, High drug loading, Hot-melt extrusion, Orodispersible tablets, Stability, Surface dissolution imaging,
- MeSH
- 3D tisk * MeSH
- farmaceutická technologie metody MeSH
- flukonazol * MeSH
- poréznost MeSH
- tablety chemie MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- flukonazol * MeSH
- tablety MeSH
An active pharmaceutical ingredient (API) is any substance in a pharmaceutical product that is biologically active. That means the specific molecular entity is capable of achieving a defined biological effect on the target. These ingredients need to meet very strict limits; chemical and optical purity are considered to be the most important ones. A continuous-flow synthetic methodology which utilizes a continuously flowing stream of reactive fluids can be easily combined with photochemistry, which works with the chemical effects of light. These methods can be useful tools to meet these strict limits. Both of these methods are unique and powerful tools for the preparation of natural products or active pharmaceutical ingredients and their precursors with high structural complexity under mild conditions. This review shows some main directions in the field of active pharmaceutical ingredients' preparation using continuous-flow chemistry and photochemistry with numerous examples of industry and laboratory-scale applications.
- Klíčová slova
- active pharmaceutical ingredients, flow chemistry, photochemistry,
- MeSH
- biologické přípravky * MeSH
- farmaceutická technologie * metody MeSH
- léčivé přípravky MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Názvy látek
- biologické přípravky * MeSH
- léčivé přípravky MeSH
In direct compression of tablets, it is crucial to maintain content uniformity within acceptable margins, especially in formulations with low drug loading. To assure it, complex and multistep mixing processes are utilized in the industry. In this study, we suggest the use of a simple segregation test to evaluate mixing process performance and mixture segregation to produce tablets having satisfying content uniformity while keeping the process as simple and low cost as possible. Eventually, the formulation propensity to segregation can be evaluated using process analytical technology (PAT) to adjust the mixing process parameters to changing source drug properties. In this study, that approach was examined on a model drug with a broad batch-to-batch variability in particle size and shape. Excipients were chosen so that the resulting blend composition mimicked some marketed formulations. For each drug batch, two formulation blends were prepared through different preparation processes (one simple and one complex) and subsequently subjected to segregation tests. From those, segregation coefficients were obtained to compare segregation tendencies and homogeneity robustness between the drug batches and the blend preparation methods. The inter-particulate interactions were substantially influenced by the drug particle morphology and size and resulted in different segregation behavior. Based on these findings, a simple segregation test proved to be a useful tool for determining the suitability of different batches of the model drug to be used in a certain formulation. Moreover, for a particular batch A, the test revealed a potential for mixing process simplification and therefore process intensification and cost reduction.
- Klíčová slova
- batch-to-batch variability, direct tablet compression, mixing process, segregation, segregation test,
- MeSH
- farmaceutická technologie metody MeSH
- pomocné látky chemická syntéza MeSH
- prášky, zásypy, pudry MeSH
- příprava léků metody MeSH
- tablety MeSH
- tlak MeSH
- velikost částic * MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- pomocné látky MeSH
- prášky, zásypy, pudry MeSH
- tablety MeSH
Despite the increasing interest in pharmaceutical use of mesoporous silica, there is still only limited knowledge on mechanisms of pore loading and subsequent drug desorption and release. Hence the aim of this work was to address the mechanistic aspects of drug loading into the mesoporous silica pores and to minimise the risk of pore clogging. Hydrophilic solvents (polysorbate 20 and polyethylene glycol 200) with high dissolving capacity for the model drug celecoxib were studied for their surface tension as well as dynamic viscosity by considering hydration. As an innovation in liquisolid systems preparation, a rather simple drug loading method on a mesoporous carrier was introduced by using semi-volatile solvent mixtures. Fast liquid loading into the pores was achieved due to the lowered viscosity and surface tension of the whole solvent system. Drug release kinetics suggested that lipid-based formulations belonging to class IV of Lipid Formulation Classification System may exhibit a lower risk of incomplete desorption from a carrier. The utilisation of volatile solvents during preparation had no negative impact on the liquisolid systems' dissolution behaviour. All prepared formulations showed similar significantly faster dissolution profiles compared to the physical mixture. The novel approach has potential to promote liquisolid applications in pharmaceutics.
- Klíčová slova
- Drug loading, Liquisolid systems, Mesoporous silica, Poor solubility, Semi-volatile mixture, Syloid XDP,
- MeSH
- diferenciální skenovací kalorimetrie metody MeSH
- farmaceutická chemie metody MeSH
- farmaceutická technologie metody MeSH
- hydrofobní a hydrofilní interakce MeSH
- kinetika MeSH
- léčivé přípravky chemie MeSH
- lipidy chemie MeSH
- nosiče léků chemie MeSH
- oxid křemičitý chemie MeSH
- polysorbáty chemie MeSH
- propylenglykol chemie MeSH
- rozpouštědla chemie MeSH
- rozpustnost účinky léků MeSH
- tablety chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- léčivé přípravky MeSH
- lipidy MeSH
- nosiče léků MeSH
- oxid křemičitý MeSH
- polysorbáty MeSH
- propylenglykol MeSH
- rozpouštědla MeSH
- tablety MeSH
Despite several shortcomings such as extreme hydrophobicity, low drug capacity, characteristic triphasic drug release pattern with a high burst effect, poly(lactic-co-glycolic acid derivatives are widely used in drug delivery. Most frequent attempts to improve their properties are blending with other polymers or synthesis of block copolymers. We introduce a new class of branched poly(lactic-co-glycolic acid) derivatives as promising biodegradable carriers for prolonged or targeted drug release systems, employed as thin adhesive films, solid dispersions, in situ forming implants or nanoparticles. A series of poly(lactic-co-glycolic acid) derivatives with lower molar mass and star or comb architecture were synthesized by a simple, catalyst free, direct melt polycondensation method not requiring purification of the obtained sterile product by precipitation. Branching monomers used were mannitol, pentaerythritol, dipentaerythritol, tripentaerythritol and polyacrylic acid. The products were characterized by molar mass averages, average branching ratio, rheological and thermal properties.
- Klíčová slova
- PLGA, branching, light scattering, polymer synthesis, star polymer,
- MeSH
- farmaceutická chemie metody MeSH
- farmaceutická technologie metody MeSH
- hydrofobní a hydrofilní interakce MeSH
- kopolymer kyseliny glykolové a mléčné chemie MeSH
- lékové transportní systémy * MeSH
- nosiče léků chemie MeSH
- reologie MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kopolymer kyseliny glykolové a mléčné MeSH
- nosiče léků MeSH
The aim of this study was to prepare benzydamine hydrochloride loaded orodispersible films using modified semisolid extrusion 3D printing method. An innovative approach was developed where thin layer of drug loaded dispersion is printed and dried before printing of subsequent layers. Layer-by-layer drying as the in process step improves mechanical properties of films, uniformity of drug content and allows faster preparation of films in compounding settings due to shortening of drying time. Orodispersible films consisted of film forming maltodextrin, sorbitol as a plasticizer and hydroxyethylcellulose as a thickening agent. The height of the digital model showed excellent correlation with the disintegration time, weight, thickness and mechanical properties of prepared films. Drug content, predefined by volume of digital model and concentration of drug in print dispersion, showed excellent uniformity. The modified printing method shows great promise in a compounding production of personalized film dosage forms, and brings in possibilities such as one step preparation of films with compartmented drugs and incorporation of taste masking or release control layers.
- Klíčová slova
- 3D printing, Benzydamine hydrochloride, Multilayer, Orodispersible films, Personalization,
- MeSH
- 3D tisk * MeSH
- benzydamin chemie MeSH
- celulosa analogy a deriváty chemie MeSH
- farmaceutická technologie metody MeSH
- lékové transportní systémy * MeSH
- pomocné látky chemie MeSH
- viskozita MeSH
- vysoušení MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- benzydamin MeSH
- celulosa MeSH
- hydroxyethylcellulose MeSH Prohlížeč
- pomocné látky MeSH
