Manufacturing process transfer to a 30 kg/h continuous direct compression line with real-time composition monitoring.

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.

Analytical comparison between batch and continuous direct compression processes for pharmaceutical manufacturing using an innovative UV-Vis reflectance method and chemometrics.

Advancements in industrial technologies and the application of quality by design (QbD) guidelines are shifting the attention of manufacturers towards innovative production techniques. In the pharmaceutical field, there is a significant focus on the implementation of continuous processes, in which the production stages are carried out continuously, without the need to interrupt the process and store the production intermediates, as in traditional batch production. Such innovative production techniques also require the development of proper analytical methods able to analyze the products in-line, while still being processed. The present study aims to compare a traditional batch manufacturing process with an alternative continuous one. To this end, a real pharmaceutical formulation was used, substituting the active pharmaceutical ingredient (API) with riboflavin, at the concentration of 2 %w/w. Moreover, a direct and non-destructive analytical method based on UV-Vis reflectance spectroscopy was applied for the quantification of riboflavin in the final tablets, and compared with a traditional absorbance analysis. Good results were obtained in the comparison of both the two manufacturing processes and the two analytical methods, with R2 higher than 0.9 for all the calculated calibration models and predicted riboflavin concentrations that never significantly overcame the 15 % limits recommended by the pharmacopeia. The continuous production method demonstrated to be as reliable as the batch one, allowing to save time and money in the production step. Moreover, UV-Vis reflectance was proved to be an interesting alternative to absorption spectroscopy, which, with the proper technology, could be implemented for in-line process control.

Utilization and Evaluation of Rice Bran and Rice Bran Wax as a Tablet Lubricant.

The rice bran and rice bran wax of the KJ CMU107 rice strain were investigated as potential tablet lubricants in a directly compressed tablet formulation. Stabilized full-fatted rice bran (sFFRB), stabilized defatted rice bran (sDFRB), and rice bran wax (RBW) extracted and purified from crude rice bran oil (cRBO) were tested. Two commercial lubricants, including magnesium stearate (MGS) and hydrogenated cottonseed oil (HVO), were employed as the standards in the formulated mixtures, which contained spray-dried rice starch (SDRS) as a diluent. The tableting was carried out for each formulation, and the obtained tablets were physically and mechanically evaluated. Among the parameters investigated were the general appearance, ejection force, weight variation, hardness, friability, and disintegration time. The powder flow was also determined for each formulation. The results showed that the tablet ejection forces for all the lubricated formulations (58-259 N) were significantly lower than that of the non-lubricated control formulation (349 N). The use of sFFRB as a lubricant at 0.5-2.0% w/w could lower the ejection force up to 78%, but the hardness reduced so drastically that the formulations failed the friability test due to the chipping of the tablets' edges. Moreover, sDFRB performed significantly better as the use at 0.5-1.0% w/w in the formulation helped to lower the ejection forces by up to 80% while maintaining the changes in the tablet hardness within 10%. RBW functioned effectively as a tablet lubricant at a concentration of 0.5% w/w, yielding tablets with good strength comparable to standard HVO lubricant while helping to reduce the ejection force by 82%. In formulations with good lubrication, i.e., friability < 1%, the powder flow was improved, and the tablet disintegration times were within the same range as the control and HVO formulations. In conclusion, sDFRB displayed a lubricant property at concentrations between 0.5 and 1.0% w/w, with slightly negative effects on the tablet hardness. RBW from KJ CMU107 rice was an effective tablet lubricant at 0.5% w/w, with no effect on tablet hardness. Both materials can be further developed for use as commercial lubricants in direct compression.

Application of the SeDeM system for the preparation of antiparasitic tablets from mesquite flour for use in sheep.

The use of herbal medicine to treat various diseases is becoming increasingly important as an alternative therapy. Numerous plants have been traditionally used for different purposes, including antiparasitic in humans and animals. Diseases caused by gastrointestinal parasites in ruminants, especially by the nematode Haemonchus contortus, cause large economic losses to the producers, whether by complications of the diseases or the cost of treatment. The main way of handling nematodiasis is by administering anthelmintic drugs, but their excessive use has the disadvantage of causing drug resistance; therefore, an alternative is the use of herbal medicine for this purpose. Mesquite (Prosopis spp.) has been used in Mexico to treat gastrointestinal diseases attributed to helminths. The present study aimed to characterize the rheological properties of mesquite flour using the SeDeM Expert System to determine its suitability for tablet production by direct compression. Direct compression technology facilitates the tableting process by reducing manufacturing costs. The results of the present study indicate that mesquite flour can be processed by direct compression. The latter could allow the manufacturing of economic tablets to treat infections by H. contortus in ruminants.

Trace polymer coated clarithromycin spherulites: Formation mechanism, improvement in pharmaceutical properties and development of high-drug-loading direct compression tablets.

Clarithromycin (CLA) is a high dose antibiotic drug exhibiting poor flowability and tabletability, making the tablet development challenging. This study aims to develop spherulitic CLA by introducing trace amount of polymer in crystallization solution. Its formation mechanism, physicochemical properties and potential for the direct compression (DC) tablets development were also investigated. Morphological analyses and the in situ observation on crystallization process revealed that the CLA spherulites are formed by fractal branching growth from both sides of the threadlike precursor fibers. 1H NMR analysis and nucleation time monitoring indicated that the existence of hydroxypropyl cellulose in solution slowed down the crystal nucleation and growth rate by forming hydrogen bonding interactions with CLA molecules, making the system maintain high supersaturation, providing high driving forces for CLA spherulitic growth. In comparison to commercial CLA, the CLA spherulites exhibit profoundly improved flowability, tabletability and dissolution behaviors. XPS, contact angle and Raman mapping analysis confirmed the presence of a thin HPC layer on the surfaces and interior of CLA spherulitic particles, resulting in increasing powder plasticity, interparticulate bonding strength and powder wettability, thus better tabletability and dissolution performances. The improved flowability and tabletability of CLA spherulites also enabled the successful development of DC tablet formulation with a high CLA loading (82.8 wt%) and similar dissolution profiles to reference listed drug. This study provides a novel solid form of CLA with superior manufacturability for further development.

Batch vs. continuous direct compression - a comparison of material processability and final tablet quality.

In this study, an in-depth comparison was made between batch and continuous direct compression using similar compression set-ups. The overall material processability and final tablet quality were compared and evaluated. Correlations between material properties, process parameters and final tablet properties were made via multivariate data analyses. In total, 10 low-dosed (1% w/w) and 10 high-dosed (40% w/w) formulations were processed, using a total of 10 different fillers/filler combinations. The trials indicated that the impact of filler type, drug load or process settings was similar for batch and continuous direct compression. The main differentiator between batch and continuous was the flow dynamics in the operating system, where properties related to flow, compressibility and permeability played a crucial role. The less consistent flow throughout a batch process resulted in a significantly higher variability within the tablet press (σCF) and for the tablet quality responses (σMass, σTS). However, the better controlled blending procedure prior to batch processing was reflected in a more consistent API concentration variability. Overall, the comparison showed the benefits of selecting appropriate excipients and process settings to achieve a specific outcome, keeping in mind some key differentiators between both processes.

Using AI/ML to predict blending performance and process sensitivity for Continuous Direct Compression (CDC).

Utilising three artificial intelligence (AI)/machine learning (ML) tools, this study explores the prediction of fill level in inclined linear blenders at steady state by mapping a wide range of bulk powder characteristics to processing parameters. Predicting fill levels enables the calculation of blade passes (strain), known from existing literature to enhance content uniformity. We present and train three AI/ML models, each demonstrating unique predictive capabilities for fill level. These models collectively identify the following rank order of feature importance: RPM, Mixing Blade Region (MB) size, Wall Friction Angle (WFA), and Feed Rate (FR). Random Forest Regression, a machine learning algorithm that constructs a multitude of decision trees at training time and outputs the mode of the classes (classification) or mean prediction (regression) of the individual trees, develops a series of individually useful decision trees. but also allows the extraction of logic and breakpoints within the data. A novel tool which utilises smart optimisation and symbolic regression to model complex systems into simple, closed-form equations, is used to build an accurate reduced-order model. Finally, an Artificial Neural Network (ANN), though less interrogable emerges as the most accurate fill level predictor, with an r2 value of 0.97. Following training on single-component mixtures, the models are tested with a four-component powdered paracetamol formulation, mimicking an existing commercial drug product. The ANN predicts the fill level of this formulation at three RPMs (250, 350 and 450) with a mean absolute error of 1.4%. Ultimately, the modelling tools showcase a framework to better understand the interaction between process and formulation. The result of this allows for a first-time-right approach for formulation development whilst gaining process understanding from fewer experiments. Resulting in the ability to approach risk during product development whilst gaining a greater holistic understanding of the processing environment of the desired formulation.

Novel bioequivalent oral disintegrating tablet of aripiprazole prepared by direct compression technique with shortened disintegration time.

Herein, we aimed to formulate a novel oral disintegrating tablet (ODT) of aripiprazole (ARP) capable of rapid disintegration using a direct compression technique. Different ODTs were fabricated with directly compressible excipients, and their disintegration time, wettability (water absorption ratio and wetting time), and mechanical properties (hardness and friability) were evaluated. The optimized ODT comprised F-Melt® type C, Prosolv® SMCC HD90, and Na croscarmellose (10 mg of ARP in a 130 mg tablet). The ODT with 3.1-5.2 kp hardness exhibited rapid disintegration (14.1-17.2 sec), along with appropriate mechanical strength (friability < 0.24%). In a bioequivalent study in Korean healthy subjects (randomized, single-dose, two-period crossover design, n = 37), the novel ODT offered the equivalent pharmacokinetic profile to that of a conventional immediate release tablet (Otsuka, Abilify®, Japan), despite different disintegration and dissolution profiles. The 90% confidence intervals of the geometric mean test to reference ratios considering the area-under-the-curve and maximum plasma drug concentrations were 1.0306-11051 and 0.9448-1.1063, respectively, satisfying FDA regulatory criteria for bioequivalence. The novel ART ODT was physicochemically stable under the accelerated storage condition (40 °C, RH75%) for 24 weeks. Therefore, the novel ARP-loaded ODT is expected to be an alternative to oral ARP therapy, providing improved patient adherence.

Elucidating the Impact of Material Properties on Tablet Manufacturability for Binary Paracetamol Blends.

PURPOSE: Although the mechanical properties of paracetamol and MCC are extensively described in literature, there still is a need for a better understanding of the material properties impacting them. Thus, this study systematically analyzed material properties of paracetamol-MCC blends to elucidate their influence on the mechanical tablet properties in roller compaction and direct compression with special focus on surface properties. METHODS: Multiple material characteristics of binary mixtures of paracetamol and MCC with varying drug loads were analyzed, with particular emphasis on specific surface area and surface energy. Subsequently, mechanical tablet properties of the materials in direct compression and after roller compaction were examined. RESULTS: It was demonstrated that the impact of the initial material properties on mechanical tablet properties prevailed over the impact of processing route for paracetamol-MCC blends, underlining the importance of material characterization for tabletability of oral solid dosage forms. By applying bivariate as well as multivariate analysis, key material properties influencing the tabletability of paracetamol, MCC and its mixtures such as surface area, surface energy, effective angle of internal friction and density descriptors were identified. CONCLUSIONS: This study highlighted the importance of comprehensive assessment of different material characteristics leading to a deeper understanding of underlying factors impacting mechanical tablet properties in direct compression and after roller compaction by the example of paracetamol-MCC mixtures with varying drug loads. Furthermore, it was shown that multivariate analysis could be a valuable extension to common bivariate analysis to reveal underlying correlations of material properties.

A Commentary on Co-Processed API as a Promising Approach to Improve Sustainability for the Pharmaceutical Industry.

Pharmaceutical products represent a meaningful target for sustainability improvement and emissions reduction. It is proposed here that rethinking the standard, and often linear, approach to the synthesis of Active Pharmaceutical Ingredients (API) and subsequent formulation and drug product processing will deliver transformational sustainability opportunities. The greatest potential arguably involves API that have challenging physico-chemical properties. These can require the addition of excipients that can significantly exceed the weight of the API in the final dosage unit, require multiple manufacturing steps to achieve materials amenable to delivering final dosage units, and need highly protective packaging for final product stability. Co-processed API are defined as materials generated via addition of non-covalently bonded, non-active components during drug substance manufacturing steps, differing from salts, solvates and co-crystals. They are an impactful example of provocative re-thinking of historical regulatory and quality precedents, blurring drug substance and drug product operations, with sustainability opportunities. Successful examples utilizing co-processed API can modify properties with use of less excipient, while simultaneously reducing processing requirements by delivering material amenable to continuous manufacturing. There are also opportunities for co-processed API to reduce the need for highly protective packaging. This commentary will detail the array of sustainability impacts that can be delivered, inclusive of business, regulatory, and quality considerations, with discussion on potential routes to more comprehensively commercialize co-processed API technologies.

Development of a novel direct compressible co-processed excipient and its application for formulation of Mirtazapine orally disintegrating tablets.

INTRODUCTION: Orally disintegrating tablets (ODTs) are designed to dissolve in the oral cavity within 3 min, providing a convenient option for patients as they can be taken without water. Direct compression is the most common method used for ODTs formulations. However, the availability of single composite excipients with desirable characteristics such as good compressibility, fast disintegration, and a good mouthfeel suitable for direct compression is limited. OBJECTIVE: This research was proposed to develop a co-processed excipient composed of xylitol, mannitol, and microcrystalline cellulose for the formulation of ODTs. METHODS: A total of 11 formulations of co-processed excipients with different ratios of ingredients were prepared, which were then compressed into ODTs, and their characteristics were thoroughly examined. The primary focus was on evaluating the disintegration time and hardness of the tablets, as these factors are important in ensuring the ODTs meet the desired criteria. The model drug, Mirtazapine was then incorporated into the chosen optimized formulation. RESULTS: The results showed that the formulation comprised of 10% xylitol, 10% mannitol and 80% microcrystalline cellulose demonstrated the fastest disintegration time (1.77 ± 0.119 min) and sufficient hardness (3.521 ± 0.143 kg) compared to the other formulations. Furthermore, the drug was uniformly distributed within the tablets and fully released within 15 min. CONCLUSION: Therefore, the developed co-processed excipients show great potential in enhancing the functionalities of ODTs, offering a promising solution to improve the overall performance and usability of ODTs in various therapeutic applications.

Effect of Powdered Cellulose Nanofiber with Different Particle Sizes on the Physical Properties of Tablets Manufactured via Direct Compression.

Direct compression is a tableting technique that involves a few steps in non-demanding manufacturing conditions. High strength and rapid disintegration of tablet formulations were previously achieved through the addition of cellulose nanofibers (CNFs), which have recently attracted attention as a high-performance biomass material. However, CNF addition results in greater variation in tablet weight and drug content, potentially due to differences in particle size between CNF and other additives. Herein, we used pulverized CNF to evaluate the effect of CNF particle size on the variation in tablet weight and drug content. Tablet formulations consisted of CNF with different particle sizes (approximately 100 µm [CNF100] and 300 µm [CNF300], at 0, 10, 30, or 50%), lactose hydrate, acetaminophen, and magnesium stearate. Ten powder formulations with different particle sizes and CNF concentrations were prepared; thereafter, the tablets were produced using a rotary tableting press with a compression force of 10 kN. The variation in weight and drug content as well as the tensile strength, friability, disintegration time, and drug dissolution of tablets were evaluated. CNF100 addition to the tablets reduced the weight and drug content variation to a greater extent than CNF300 addition. Using CNF300, we produced tablets of sufficient strength and short disintegration time. These properties were also achieved with CNF100 addition. Our findings suggest that adding CNF of small particle size to the tablet formulation can reduce the variation in weight and drug content while maintaining high strength and short disintegration time.

Lubricant Sensitivity of Direct Compression Grades of Lactose in Continuous and Batch Tableting Process.

Modern pharmaceutical manufacturing based on Quality by Design and digitalisation is revolutionising the pharmaceutical industry. Continuous processes are promoted as they increase efficiency and improve quality control. Compared to batch blending, continuous blending is easier to scale and provides advantages for achieving blend homogeneity. One potential challenge of continuous blending is the risk of over-lubrication. In this study, blending homogeneity and lubricant sensitivity are investigated for both batch and continuous processes. Given their distinct chemical structures and morphologies, anhydrous lactose and granulated lactose are expected to exhibit varying sensitivities to changes in process settings across both technologies. The findings suggest that both lactose grades provide highly stable blends that can be safely utilised in both batch and continuous modes. Optimisation should focus on process variables, such as the quality of loss-in-weight feeders used for dosing low doses of ingredients. The most significant process parameter for lubricant sensitivity was the type of lactose used. Anhydrous lactose produced harder tablets than the more porous granulated lactose but was more sensitive to lubrication at the same settings. The magnesium stearate content and its interaction with the type of lactose are also critical factors, with magnesium stearate having a counterproductive impact on tabletability.

Challenges in the transfer and scale-up of mini-tableting: Case study with losartan potassium.

Mini-tablets (MTs) with losartan potassium were developed to treat the rare disease Epidermolysis Bullosa. The focus was placed on transfer and scale-up of a direct compressible formulation from the compaction simulator STYL'One Evo (CS) to the rotary tablet press Korsch XM 12 (RP). Transfer of tabletability and compactibility profiles from CS to RP did not show good agreement, e.g. at a tableting pressure of 125 MPa mean tensile strengths (TS) of 4 MPa on CS and 1-1.5 MPa on RP were reached. These results highlight the impact of the feed frame on final product qualities depending on process and material factors. In the scale-up studies the critical quality attributes (CQAs) mass variation, content uniformity, TS and disintegration time were investigated. After an appropriate run-up time, most CQAs reached a plateau, after reaching a balance between influx, efflux and distribution of lubricant in the feed frame. TS values of 1-2 MPa, disintegration times of max. 50 s, mass variation of 0.9-2.2 % (CV) and acceptance values below 15.0 were reached depending on chosen process parameters.

Development of a formulation of potassium iodide tablets as an antidote against nuclear incidents.

Objectives: Potassium iodide (KI) is a treatment to neutralize radioactive agents that could be inhaled or ingested in nuclear incidents. The inorganic salt KI constitutes a source of iodine, which in the body acts by accumulating in the thyroid gland, producing its saturation, and thus preventing the fixation of radioactive iodine species. In Spain, the Military Defence Pharmacy Centre (CEMILFARDEF) was challenged to develop this antidote to be distributed among the population surrounding nuclear power plants, in only one new solid pharmaceutical form for oral administration, in order to replace the two pharmaceutical forms available, which are capsules for adults and oral solution for children, considered less versatile. Methods: A selection of excipients was carried out to achieve pharmacotechnical behaviour suitable for the industrial manufacture of potassium iodide in tablets, complying with the pre-established process and finished product quality parameters. The development allowed the preparation of three industrial-sized batches on which the stability of the developed formulation was studied. Results: An uncoated 65 mg double-scored potassium iodide tablet was developed using easily accessible excipients in the formulation and direct compression as the manufacturing method. The formula complied with the stability tests, with which the development carried out can respond to the eventual demand that its elaboration would entail in the event of nuclear incidents. Conclusions: The developed formulation of a 65 mg double-scored potassium iodide tablet allows the great variability of user needs, from infants to adults with a single pharmaceutical form, which additionally implies logistical benefits in distribution, stock control and appropriate renewal according expiration dates, among the population surrounding nuclear power plants and available to deployed military personnel, in the event of potential nuclear incidents.

Segregation of formulated powders in direct compression process and evaluations by small bench-scale testers.

Powder segregation can cause severe issues in processes of pharmaceutical drugs for control of content uniformity if the powder is likely to be free or easy flowing. Assessing segregation intensity of formulated powders in a process is challenging at the formulation stage because of the limited availability of samples. An advanced segregation evaluation using small bench-scale testers can be useful for formulation decisions and suggestions of operation conditions in the process, which has not been practically investigated before. In this study, eight formulations (two co-processed excipients blended with one active pharmaceutical ingredient at different ratios) were used for the segregation study on two types of bench-scale testers (air-induced and surface rolling segregation tester), and a pilot simulation process rig as a comparative study. The results show that segregation measured on the bench-scale testers can give a good indication of the segregation intensity of a blend if the segregation intensity is not more than 20%. The comparison also shows that both the bench-scale testers have a good correlation to the process rig, respectively, which means either segregation tester can be used independently for the evaluation. A linear regression model was explored for prediction of segregation in the process.

Application of co-precipitated glutinous rice starch as a multifunctional excipient in direct compression tablets.

Two key properties of excipients for inclusion in direct compression tablets are flowability and compactibility. Glutinous rice starch (GRS) has poor flowability, which limits its use in direct compression tablets. This study aimed to create a multifunctional direct compression excipient (filler binder disintegrant) with improved flowability from GRS by the co-precipitation method. The physicochemical and pharmaceutical properties of the co-precipitated GRS (cpGRS) were investigated. The optimum conditions for producing cpGRS (0.43 M sodium hydroxide solution, 7.09% PVP K30, 14.02% calcium carbonate, 95 min of mixing time and pH of 6.97) resulted in 68.80% yield, fair to good flowability, acceptable tablet strength, and fast disintegration. The FT-IR spectra of cpGRS showed no significant shifts in the key peaks, which indicates that there was an absence of chemical interactions within cpGRS. X-ray diffractograms also showed no significant changes, indicating that the GRS granules, calcium carbonate, and PVP K30 components remained unaltered during co-precipitation. cpGRS also demonstrated a dilution capacity of 50% when paracetamol was used as model drug. When cpGRS was combined with domperidone or propranolol hydrochloride it showed a better deformation capability than the physical mixtures. Although cpGRS was sensitive to lubricant, the hardness and tensile strength were higher than common strength for general purpose use in tablets. When compared to the physical mixture, pregelatinized starch and directly compressible calcium carbonate, the results showed that cpGRS tablets of both model drugs passed the friability test, demonstrated the best disintegration property, provided the fastest and highest drug release profile for propranolol, and improved the drug release profile for domperidone. For propranolol-cpGRS tablets, dissolution medium at different pH did not affect the dissolution profile. For domperidone-cpGRS tablets, the pH of dissolution medium did affect the dissolution profile of the tablets. This was according to the API solubility. These results reveal that cpGRS is an excellent multifunctional i.e., filler, binder, and disintegrant excipient suitable for direct compression tablets. The main component is natural. The preparation method is simple, quick, and efficient. This method does not produce harmful waste and requires only basic equipment, and affordable reactants and devices.

Application of Positron Emission Particle Tracking (PEPT) for the evaluation of powder behaviour in an incline linear blender for Continuous Direct Compression (CDC).

Positron Emission Particle Tracking (PEPT) is a non-invasive measurement technique which offers the ability to track the motion of individual particles with high temporal and spatial resolution, and thus build up an understanding of the bulk behaviour of a system from its microscopic (particle level) dynamics. Using this measurement technique, we have developed a series of novel metrics to better understand the behaviours of powders during the steady-state operation of a continuous blender system. Results are presented concerning the response of particle motion to processing parameters (mixing blade configuration and RPM), quantifying the motion in terms of predicted mixing performance. It was found that both increasing rpm and increasing hold-up mass (by selecting fewer transport blades and more mixing blades) provided improved mixing conditions. Interestingly, under specific conditions, there is evidence of convection-like mixing occurring at the interface of the transport and mixing region. This suggests the existence of a potential 'folding region' whereby powder is transported up the barrel (and away from the powder bulk bed) before being reconstituted back into the bulk mass. The results also provide valuable experimental data for the development, calibration and validation of future Discrete Element Method (DEM) simulations.

Investigating the Impact of Co-processed Excipients on the Formulation of Bromhexine Hydrochloride Orally Disintegrating Tablets (ODTs).

PURPOSE: Orodispersible tablets (orally disintegrating tablets, ODTs) have been used in pharmacotherapy for over 20 years since they overcome the problems with swallowing solid dosage forms. The successful formula manufactured by direct compression shall ensure acceptable mechanical strength and short disintegration time. Our research aimed to develop ODTs containing bromhexine hydrochloride suitable for registration in accordance with EMA requirements. METHODS: We examined the performance of five multifunctional co-processed excipients, i.e., F-Melt® C, F-Melt® M, Ludiflash®, Pharmaburst® 500 and Prosolv® ODT G2 as well as self-prepared physical blend of directly compressible excipients. We tested powder flow, true density, compaction characteristics and tableting speed sensitivity. RESULTS: The manufacturability studies confirmed that all the co-processed excipients are very effective as the ODT formula constituents. We noticed superior properties of both F-Melt's®, expressed by good mechanical strength of tablets and short disintegration time. Ludiflash® showed excellent performance due to low works of plastic deformation, elastic recovery and ejection. However, the tablets released less than 30% of the drug. Also, the self-prepared blend of excipients was found sufficient for ODT application and successfully transferred to production scale. Outcome of the scale-up trial revealed that the tablets complied with compendial requirements for orodispersible tablets. CONCLUSIONS: We proved that the active ingredient cannot be absorbed in oral cavity and its dissolution profiles in media representing upper part of gastrointestinal tract are similar to marketed immediate release drug product. In our opinion, the developed formula is suitable for registration within the well-established use procedure without necessity of bioequivalence testing.

Formulation and Development of Flurbiprofen Colon-Specific Eudragit Coated Matrix Tablets: Use of a Novel Crude Banana Peel Powder as a Time-Dependent Polymer.

The rationale for the current investigation is to study the crude banana peel (CBP) powder efficiency as a novel natural time-dependent polymer along with a pH-sensitive polymer to develop flurbiprofen colon-specific tablets. The direct compression method is utilized to prepare the flurbiprofen-CBP matrix tablets using 9 mm punches on the rotary tableting machine and subsequently coated with Eudragit® S 100 by a dip coating method. The tablets were evaluated for various tableting properties and in vitro drug release studies. From the results of dissolution studies, the F6 formulation showed negligible drug release (5.76% in 5 h) in the upper gastrointestinal tract and progressive release in the colon (99.08% in 24 h). Mean dissolution time, T10%, and T80% were found to be 13.33 h, 5.8 h, and 20.7 h, respectively, which explains the efficiency of the present combination of polymers for colon-specific drug release. From the dissolution studies results of stability studies, the similarity index was calculated and found to be 74.75. In conclusion, utilizing CBP as a natural, time-dependent polymer in conjunction with Eudragit® S 100 to develop the flurbiprofen tablets seems like a promising approach for delivering drugs specifically to the colon.