The interplay of poorly soluble drugs in dissolution from amorphous solid dispersions.

In recent years, the application of fixed dose combinations of antiretroviral drugs in HIV therapy has been established. Despite numerous therapeutic benefits, this approach poses several challenges for the formulation development especially when poorly soluble drugs are considered. Amorphous solid dispersions (ASD) thereby have gained considerable interest in the pharmaceutical field, however, mainly including binary systems containing only one drug and a polymer. The co-formulation of two amorphous drugs can be accompanied by an immense increase in the complexity of the system as exemplarily reported for ritonavir and lopinavir embedded in a composite polymer matrix of PVPVA. The present study aims to present a new formulation approach to overcome the well-documented interaction during dissolution. Two different polymers, PVPVA and HPMCAS were used to produce ASDs for both drugs individually via hot-melt extrusion. The embedding of lopinavir in the slower dissolving polymer HPMCAS, while using PVPVA for ritonavir was found to significantly improve the overall dissolution performance compared to the individual use of PVPVA as well as to the commercial product Kaletra®. In addition, the use of different grades of HPMCAS demonstrated the possibility to further modify the dissolution profile. For a preliminary biorelevant assessment, the selected formulations were tested in a biphasic dissolution setup.

Genesis, mechanism, and avoidance of cosmetic coating defects - An industrial case study.

Film-coated tablets as solid oral dosage forms are a well-accepted way of administering drugs but are not without specific challenges during manufacturing. One relevant criterion of the final product is the visual integrity and therewith, the absence of cosmetic optical defects such as edge chipping. The aim of the present study was to examine the origin of those edge chipping defects, which were observed during commercial manufacturing of film-coated tablets, and to provide recommendations for process optimization to reduce the defect occurrence. The unraveling of the herein described phenomenon necessitated an interplay of in-depth material characterization, discrete element modeling (DEM) as well as an in-house developed optical measurement system for the automated quantification of tablet defects. As a result of this investigation, the automatic unloading step after the tablet coating process was identified as the most critical step for the occurrence of chipping defects and a replacement by manual unloading was proposed to reduce the defect propensity. The recommended optimization was subsequently confirmed in several manufacturing runs and a reduction of defect propensity by a factor of 5 was observed, highlighting the relevance and the impact of the performed thorough investigation.

Downstream processing of amorphous solid dispersions into orodispersible tablets.

The formulation development of amorphous solid dispersions (ASDs) towards a patient-friendly oral solid dosage form is proving to be still challenging. To increase patient's compliance orodispersible tablets (ODTs) can be seen as promising alternative. Two different ASDs were prepared via hot melt extrusion (HME), using PVPVA as polymer for ritonavir (RTV) and HPMCAS for lopinavir (LPV). The extrudates were milled, sieved, and blended with Hisorad® (HRD) or Ludiflash® (LF), two established co-processed excipients (CPE) prior to tableting. Interestingly, the selected ASD particle size was pointed out to be a key parameter for a fast disintegration and high mechanical strength. In terms of PVPVA based ASDs, larger particle sizes > 500 µm enabled a rapid disintegration even under 30 s for 50 % ASD loaded ODTs, whereas the use of smaller particles went along with significant higher disintegration times. However, the influence of the CPE was immense for PVPVA based ASDs, since it was only possible to prepare well performing ODTs, when Hisorad® was chosen. In contrast for HPMCAS based ASDs the selection of smaller particle sizes 180-500 µm was beneficial for overcoming the poor compressibility of the ASD matrix polymer. ODTs with LPV could be produced using both CPEs even with higher ASD loads up to 75 %, while still showing remarkably fast disintegration.

The Role of Titanium Dioxide (E171) and the Requirements for Replacement Materials in Oral Solid Dosage Forms: An IQ Consortium Working Group Review.

Titanium dioxide (in the form of E171) is a ubiquitous excipient in tablets and capsules for oral use. In the coating of a tablet or in the shell of a capsule the material disperses visible and UV light so that the contents are protected from the effects of light, and the patient or caregiver cannot see the contents within. It facilitates elegant methods of identification for oral solid dosage forms, thus aiding in the battle against counterfeit products. Titanium dioxide ensures homogeneity of appearance from batch to batch fostering patient confidence. The ability of commercial titanium dioxide to disperse light is a function of the natural properties of the anatase polymorph of titanium dioxide, and the manufacturing processes used to produce the material utilized in pharmaceuticals. In some jurisdictions E171 is being considered for removal from pharmaceutical products, as a consequence of it being delisted as an approved colorant for foods. At the time of writing, in the view of the authors, no system or material which could address both current and future toxicological concerns of Regulators and the functional needs of the pharmaceutical industry and patients has been identified. This takes into account the assessment of materials such as calcium carbonate, talc, isomalt, starch and calcium phosphates. In this paper an IQ Consortium team outlines the properties of titanium dioxide and criteria to which new replacement materials should be held.

Comparative dissolution studies of 3D-printed inserts in a novel biopharmaceutical bladder model.

Urinary tract disorders come at great discomfort to the patients suffering from them. To treat them, several potent drug substances are available but unfortunately, systemic drug therapy often comes along with undesired adverse effects. Previous work has therefore been conducted aiming at a local drug release in the urinary bladder. However, whether a therapeutically relevant drug concentration may be reached at the target site is not easy to determine when applying common compendial dissolution methods. Therefore, the aim of this study was to develop a biorelevant dissolution model able to take physiological conditions into consideration, i.e. urine flow rates, urination intervals and movement patterns during day- and nighttime. The newly developed bladder model was tested with 3D-printed intravesical inserts containing three different APIs (lidocaine hydrochloride, trospium chloride and hydrochlorothiazide) and varying the operating conditions. Although the cumulative drug release was similar to the compendial method in most cases, notable differences became apparent in the corresponding concentration profiles of all APIs. It revealed periodic concentration fluctuations in 24 h intervals due to the constantly changing volume and agitation in the bladder model. The model furthermore allowed investigating the influence of varying physiological and pathophysiological conditions on local drug release.

Impact of co-administered stabilizers on the biopharmaceutical performance of regorafenib amorphous solid dispersions.

Poor solubility of drug candidates is a well-known and thoroughly studied challenge in the development of oral dosage forms. One important approach to tackle this challenge is the formulation as an amorphous solid dispersion (ASD). To reach the desired biopharmaceutical improvement a high supersaturation has to be reached quickly and then be conserved long enough for absorption to take place. In the presented study, various formulations of regorafenib have been produced and characterized in biorelevant in-vitro experiments. Povidone-based formulations, which are equivalent to the marketed product Stivarga®, showed a fast drug release but limited stability and robustness after that. In contrast, HPMCAS-based formulations exhibited excellent stability of the supersaturated solution, but unacceptably slow drug release. The attempt to combine the desired attributes of both formulations by producing a ternary ASD failed. Only co-administration of HPMCAS as an external stabilizer to the rapidly releasing Povidone-based ASDs led to the desired dissolution profile and high robustness. This optimized formulation was tested in a pharmacokinetic animal model using Wistar rats. Despite the promising in-vitro results, the new formulation did not perform better in the animal model. No differences in AUC could be detected when compared to the conventional (marketed) formulation. These data represent to first in-vivo study of the new concept of external stabilization of ASDs. Subsequent in-vitro studies revealed that temporary exposure of the ASD to gastric medium had a significant and long-lasting effect on the dissolution performance and externally administered stabilizer could not prevent this sufficiently. By applying the co-administered HPMCAS as an enteric coating onto Stivarga tablets, a new bi-functional approach was realized. This approach achieved the desired tailoring of the dissolution profile and high robustness against gastric medium as well as against seeding.

Orodispersible tablets for pediatric drug delivery: current challenges and recent advances.

INTRODUCTION: Child appropriate dosage forms are indispensable in modern medicine and are a prerequisite for successful pediatric drug therapy. For years, experts have called for a paradigm shift, from liquid dosage forms to novel oral solid dosage forms. This review aims to shed light on recent developments in Orodispersible tablets (ODTs) and mini-tablets (ODMTs). AREAS COVERED: This review focuses on the presentation and critical discussion of current challenges as well as recent advances in ODTs for pediatric drug delivery. Highlighted aspects are the evidence for acceptability by children, e.g. in comparison to other dosage forms, and limitations given by tablet size at different ages, as well as advances in special ODT formulations (taste masking, modified release, enabling formulations). EXPERT OPINION: It is the authors' belief that OD(M)Ts have significant potential as dosage forms in pediatric therapy that has not yet been fully exploited. The reasons for this are, first, that the number of direct acceptance studies is extremely low and the resulting knowledge is therefore rather anecdotal. Despite the high relevance, there seems to be reluctance both in the therapeutic use and conduction of respective studies in children. However, if one combines the knowledge from the few existing studies, surveys, and from approved products, it becomes apparent that so far there is no evidence on limitations of the use of ODTs in pediatric patients.

Evaluation of two novel co-processed excipients for direct compression of orodispersible tablets and mini-tablets.

Pediatric, geriatric, and other patients who suffer from swallowing difficulties represent a special patient group, where an increased need in appropriate formulation development is required. To overcome these mostly swallowability linked issues, orodispersible tablets (ODTs) and orodispersible mini-tablets (ODMTs) can be seen as a suitable alternative to improve compliance. Orodispersible tablets are oral solid dosage forms which rapidly disintegrate after contact with saliva, leaving a liquid dispersion, which can be easily swallowed. To fulfil the required quality criteria and optimize the formulations regarding tensile strength and disintegration time, co-processed excipients (CPE) based on mannitol are frequently used in the manufacturing of orodispersible tablets. This study aimed to systematically compare two new CPEs, namely Granfiller-D® and Hisorad® and evaluate their potential in future OD(M)T formulations with already marketed products. The performance of the CPEs was examined in combination with three different APIs. Disintegration time, sufficient mechanical strength and content uniformity for low dosed formulation were chosen as main quality aspects. Conventionally sized tablets (9 mm) with 50% drug load of ibuprofen and paracetamol were produced with each CPE. Low dosed OD(M)Ts with a drug load of 4% enalapril maleate were manufactured to study content uniformity. Large differences were visible in the formulations containing ibuprofen and only Hisorad® allowed to compress ODT fulfilling the specifications of Ph.Eur. and FDA regarding disintegration times (180 s and 30 s, respectively). For the poorly binding model drug paracetamol, none of the studied excipients showed a satisfactory performance, with maximum tensile strengths < 1 MPa. To reach content uniformity in low dosed ODMTs, Ludiflash® seems to be the most preferable alternative, as the formulation showed the lowest acceptance values (AV) according to Ph.Eur. (<4) as well as the smallest coefficient of variation (CV) in API content (CV < 2%). In conclusion, the study revealed that none CPE is the ideal choice for all approaches, but different CPEs should be selected dependent on different challenges during formulation development of OD(M)Ts.

Alternatives to titanium dioxide in tablet coating.

Titanium dioxide (TiO2) is one of the most commonly used pharmaceutical excipients. It is widely used as a white pigment in tablet and pellet coatings. However, it has recently been under massive criticism as a number of studies suggest a cancerogenic potential. It can therefore no longer be taken for granted that TiO2 will continue to be universally available for drug products. Finding suitable alternatives is hence of special relevance. In this study, a number of different pigments were coated on tablets and their covering potential analyzed. None of the alternative pigments showed comparable effectiveness and efficiency to TiO2, though the CaCO3/CaHPO4-based coating showed the second-best results. Regarding the ability to protect photosensitive active ingredients, ZnO showed a comparable potential as TiO2, while all other pigments failed. Using the alternative pigments as markers for in-line Raman spectroscopy as a process analytical technology was challenging and led to increased prediction errors. Again, the CaCO3/CaHPO4-based coating was the only of the tested alternatives with satisfying results, while all other pigments led to unacceptably high prediction errors.

Hot-Melt Extrusion Process Fluctuations and their Impact on Critical Quality Attributes of Filaments and 3D-printed Dosage Forms.

Fused deposition modeling (FDMTM) is a 3D-printing technology of rising interest for the manufacturing of customizable solid dosage forms. The coupling of hot-melt extrusion with FDMTM is favored to allow the production of pharma-grade filaments for the printing of medicines. Filament diameter consistency is a quality of great importance to ensure printability and content uniformity of 3D­printed drug delivery systems. A systematical process analysis referring to filament diameter variations has not been described in the literature. The presented study aimed at a process setup optimization and rational process analysis for filament fabrication related to influencing parameters on diameter inhomogeneity. In addition, the impact of diameter variation on the critical quality attributes of filaments (mechanical properties) and uniformity of mass of printed drug-free dosage forms was investigated. Process optimization by implementing a winder with a special haul-off unit was necessary to obtain reliable filament diameters. Subsequently, the optimized setup was used for conduction of rational extrusion analysis. The results revealed that an increased screw speed led to diameter fluctuations with a decisive influence on the mechanical resilience of filaments and mass uniformity of printed dosage forms. The specific feed load was identified as a key parameter for filament diameter consistency.

Effect of coating time on inter- and intra-tablet coating uniformity.

Film tablets are a common oral dosage from. For many of the functions film layers can have on pharmaceutical tablets, a high degree of coating uniformity is required. In studies on coating uniformity the coefficient of variation is commonly used as a marker. Previous studies regarding the trend were mostly extrapolations from simulations of short coating times. Based on these it was stated that the inter tablet coefficient of variation decreases proportionally to one over the square root of coating time and hence diverge asymptotically towards zero. Extrapolations of experimental data suggested however a decrease converging to a residual value. Based on these results it can be hypothesized that the coefficient of variation decreases proportionally to one over time towards a residual value. Regarding intra-tablet coating homogeneity, no data on time dependency has been published so far. In this study, three long time coating experiments were performed to test the described hypotheses. The inter-tablet uniformity was derived gravimetrically, while the intra-tablet data was derived using micro-computed tomography and confocal chromatic thickness determination. Towards the end of the coating experiments, a non-zero plateau of inter-tablet uniformity was reached. Furthermore, the data showed non-random deviations from the hypothesized one-over-square-root-of-time-model. The data for intra-tablet uniformity showed a non-linear decrease as well, but did not allow falsification of either hypothesis. It was additionally found that the cap-to-band ratio was below one at short coating times and increased to values above 1 during the process, which implies that existing declarations from literature might be limited to certain process durations.

How relevant is ribbon homogeneity in roll compaction/dry granulation and can it be influenced?

A homogeneous distribution of solid fraction in ribbons is generally assumed to be beneficial during roll compaction/dry granulation. Numerous attempts have been made to increase this homogeneity by modification of the machine, i.e. the roll design and the design of the feeding unit. It has however not been critically tested how relevant this homogeneity really is during subsequent processing. This study investigated two resulting questions: How can process parameters used to increase homogeneity in ribbons and how relevant is this homogeneity for properties of resulting tablets? For that, a statistically designed experiment were performed and ribbon homogeneity analyzed using X-ray micro-computed tomography. Independent from the sealing system used during manufacturing, larger gap widths led to higher homogeneity. The effect of specific compaction force was strongly dependent on the sealing system. When using the cheek plate system, higher specific compaction forces decreased the ribbon homogeneity, while it had no influence when rim rolls were used. In a subsequent study, ribbons of different homogeneity were milled and the resulting granules compressed to tablets. Tablets from homogeneous and inhomogeneous ribbons showed comparable strength and tablet mass variability. Reduced tabletability from highly densified regions of inhomogeneous ribbons was compensated by higher amounts of fines which originate from the more porous regions of ribbons. It was concluded that the relevance of ribbon homogeneity in roll compaction might generally be overestimated.

Laser based thermo-conductometry as an approach to determine ribbon solid fraction off-line and in-line.

Ribbon solid fraction is one of the most important quality attributes during roll compaction/dry granulation. Accurate and precise determination is challenging and no in-line measurement tool has been generally accepted, yet. In this study, a new analytical tool with potential off-line as well as in-line applicability is described. It is based on the thermo-conductivity of the compacted material, which is known to depend on the solid fraction. A laser diode was used to punctually heat the ribbon and the heat propagation monitored by infrared thermography. After performing a Gaussian fit of the transverse ribbon profile, the scale parameter σ showed correlation to ribbon solid fraction in off-line as well as in-line studies. Accurate predictions of the solid fraction were possible for a relevant range of process settings. Drug stability was not affected, as could be demonstrated for the model drug nifedipine. The application of this technique was limited when using certain fillers and working at higher roll speeds. This study showed the potentials of this new technique and is a starting point for additional work that has to be done to overcome these challenges.

Impact of roll compaction design, process parameters, and material deformation behaviour on ribbon relative density.

Ribbons from microcrystalline cellulose (MCC), mannitol, and their 50:50% mixture were produced using the roll compactors AlexanderWerk BT120, Hosokawa Alpine Pharmapaktor C250, L.B. Bohle BRC 25, and Gerteis Mini-Pactor in the frame of multilevel full factorial experimental plans. The specific compaction force (SCF)/hydraulic pressure (HP), gap width (GW), roll speed, and fraction of MCC were analyzed as quantitative factors, whereas the roll surface and sealing system were examined as qualitative factors. Ribbon relative density was investigated as response of the models. The SCF/HP is found to be the most significant factor in each model. A significant inverse effect of the GW is obtained in the models of AlexanderWerk BT120, Pharmapaktor C250, and BRC 25 roll compactors, using smooth rolls. The principle of the establishment of a conversion factor (cf) is introduced based on the obtained data sets of AlexanderWerk BT120 and Mini-Pactor. This can facilitate the transfer of a roll compaction process between different types of roll compactors.