Industry's Perspective on Challenges Assessing the in Vivo Impact of Removing Titanium Dioxide (TiO2) from Drug Products.

The European Commission (EC) has tasked the European Medicines Agency (EMA) to provide a recommendation towards the acceptability of titanium dioxide (TiO2) in pharmaceutical products by early 2024 to inform on final decision in early 2025[1]. Unlike the already implemented ban of TiO2 in foods, removing this excipient from pharmaceutical products will likely have significant impact on the pharmaceutical industry, regulatory agencies, and patients. This commentary explores the challenges facing the pharmaceutical industry tasked with supporting the development and registration of TiO2 free (TF) drug products. Specifically, justification of formulation changes and potential impact to in vitro and in vivo performance, as well as differences in global regulatory comparative dissolution requirements to justify changing to TF drug product are discussed. Particularly, the uncertainties around how a formulation change such as removal of TiO2 from immediate release solid oral dosage forms will be viewed in Europe compared to other regions is discussed. To respond to these challenges and avoid disruption to the medicines supply chain in case in vitro data such as dissolution is either too challenging or insufficient to justify changing to TF product, pharmaceutical companies may have to decide if the level of risk is worth the effort needed to reformulate, develop, and register a new TF product.

Deformation Potential and Tensile Strength of Tablets of a Dry Granulated Formulation.

The increase in solid fraction (SF) of a packed granule bed with pressure applied during the in-die compression process results in an evolution of the tablet's matrix and mechanical strength. In this case study, the tensile strength (TS) of a dry granulated microcrystalline cellulose (MCC)/mannitol (MNT)-based formulation was modeled in light of the deformation potential, ∆ (tablet SF - initial granule bed SF). Results showed that the TS of tablets linearly decreased as SF of granules (produced as mini-tablets of an ibuprofen formulation) increased. The formulated granules achieved a measurable tablet strength at a slightly lower critical deformation potential (∆c) than the pure MCC granules. Beyond ∆c, tablet TS increased almost linearly as the deformation potential increased, and the rate was higher for tablets with higher SF. Compared to the simple MCC system, the granules of the MCC/MNT-based formulation were weaker, and TS of tablets increased with deformation potential at a lower rate.

Dextrose monohydrate as a non-animal sourced alternative diluent in high shear wet granulation tablet formulations.

The feasibility of dextrose monohydrate as a non-animal sourced diluent in high shear wet granulation (HSWG) tablet formulations was determined. Impacts of granulation solution amount and addition time, wet massing time, impeller speed, powder and solution binder, and dry milling speed and screen opening size on granule size, friability and density, and tablet solid fraction (SF) and tensile strength (TS) were evaluated. The stability of theophylline tablets TS, disintegration time (DT) and in vitro dissolution were also studied. Following post-granulation drying at 60 °C, dextrose monohydrate lost 9% water and converted into the anhydrate form. Higher granulation solution amounts and faster addition, faster impeller speeds, and solution binder produced larger, denser and stronger (less friable) granules. All granules were compressed into tablets with acceptable TS. Contrary to what is normally observed, denser and larger granules (at ≥21% water level) produced tablets with a higher TS. The TS of the weakest tablets increased the most after storage at both 25 °C/60% RH and 40 °C/75% RH. Tablet DT was higher for stronger granules and after storage. Tablet dissolution profiles for 21% or less water were comparable and did not change on stability. However, the dissolution profile for tablets prepared with 24% water was slower initially and continued to decrease on stability. The results indicate a granulation water amount of not more than 21% is required to achieve acceptable tablet properties. This study clearly demonstrated the utility of dextrose monohydrate as a non-animal sourced diluent in a HSWG tablet formulation.

Feasibility of mini-tablets as a flexible drug delivery tool.

Mini-tablets have potential applications as a flexible drug delivery tool in addition to their generally perceived use as multi-particulates. That is, mini-tablets could provide flexibility in dose finding studies and/or allow for combination therapies in the clinic. Moreover, mini-tablets with well controlled quality attributes could be a prudent choice for administering solid dosage forms as a single unit or composite of multiple mini-tablets in patient populations with swallowing difficulties (e.g., pediatric and geriatric populations). This work demonstrated drug substance particle size and concentration ranges that achieve acceptable mini-tablet quality attributes for use as a single or composite dosage unit. Immediate release and orally disintegrating mini-tablet formulations with 30µm to 350µm (particle size d90) acetaminophen and Compap™ L (90% acetaminophen) at concentrations equivalent to 6.7% and 26.7% acetaminophen were evaluated. Mini-tablets achieved acceptable weight variability, tensile strength, friability, and disintegration time at a reasonable solid fraction for each formulation. The content uniformity was acceptable for mini-tablets of 6.7% formulations with ≤170µm drug substance, mini-tablets of all 26.7% formulations, and composite dosage units containing five or more mini-tablets of any formulation. Results supported the manufacturing feasibility of quality mini-tablets, and their applicability as a flexible drug delivery tool.

Mechanism for enhanced absorption of a solid dispersion formulation of LY2300559 using the artificial stomach duodenum model.

An artificial stomach duodenum (ASD) model has been used to demonstrate the performance difference between two formulations of LY2300559, a low-solubility acidic developmental drug. The two formulations investigated were a conventional high-shear wet granulation (HSWG) formulation and a solid dispersion formulation. A pharmacokinetic study in humans demonstrated the enhanced performance of the solid dispersion formulation relative to the HSWG formulation. The Cmax and AUC of the solid dispersion was 2.6 and 1.9 times greater, respectively, compared to the HSWG formulation. In the ASD, the solid dispersion formulation performance was characterized by three main phases: (1) rapid release in the stomach, creating a supersaturated concentration of drug, (2) precipitation in the stomach, and (3) rapid redissolution of the precipitate in the duodenum to concentration levels that are supersaturated relative to crystalline drug. A series of complementary experiments were employed to describe this performance behavior mechanistically. Imaging experiments with a pH indicating dye showed that local pH gradients from meglumine in the solid dispersion formulation were responsible for creating a high initial supersaturation concentration in the stomach. Upon dissipation of meglumine, the drug precipitated in the stomach as an amorphous solid. Because the precipitated drug is in an amorphous form, it can then rapidly redissolve as it transits to the more neutral environment of the duodenum. This unexpected sequence of physical state changes gives a mechanistic explanation for the enhanced in vivo performance of the solid dispersion formulation relative to the HSWG formulation.

Use of artificial stomach-duodenum model for investigation of dosing fluid effect on clinical trial variability.

Lilly Compound X (LCX) is an oncology drug that was tested in a phase I clinical study using starch blend capsules. The drug was given to a small patient population (4 patients) and showed large inter- and intra-patient variability. In order to evaluate the possible effect of stomach pH on exposure and ways to mitigate the variability issue, artificial stomach-duodenum (ASD) experiments were conducted to investigate the hypothesis that carefully selected dosing fluids would have an impact in minimizing exposure variability caused by the formulation, which could lead to more consistent evaluation of drug absorption in patients. The ASD data corroborates the observed variability, and was a good tool to investigate the effect of stomach pH and potential dosing solutions on duodenal concentrations. Administering capsules co-formulated with Captisol (10% drug load) along with Sprite was shown by the ASD to be an effective way to increase duodenal concentrations as well as to reduce the difference between duodenal concentrations for different gastric pH. The reduction in variability of duodenum AUC (in ASD) is expected to correlate well with a reduction of variability in patient exposure. The dosing regimen of Sprite/Captisol is therefore suggested for future clinical trials involving LCX. Furthermore, for design of early phase clinical trials, ASD technology can be used to assist in choosing the proper dosing solution to mitigate absorption and exposure variability issues.

A novel method for estimating solid fraction of roller-compacted ribbons.

A simple method has been developed to estimate solid fraction or relative density of compacts using the weight of ribbons produced during roller compaction. The method provides an alternative to the commonly used dimensional measurement, especially for formulations not amenable to forming quality ribbons. Surface texture of the compaction rolls has been taken into consideration in our mathematical treatment along with correction for ribbon relaxation. Ribbon relaxation occurring upon ribbon exiting the compaction zone is estimated using roll geometry, roll gap, and ribbon thickness. Detailed experimental runs have been carried out to confirm the validity of the proposed theory. The predicted solid fraction was found comparable to that from actual dimensional measurement by caliper. In the case of the microcrystalline cellulose/dicalcium phosphate one:one formulation, the predicted solid fraction had an error sum of squares (SSE) of 2.64E-03 when compared to the dimensional method. When relaxation was included, the SSE decreased by four folds. Similarly, for the microcrystalline cellulose/lactose monohydrate 2:1 formulation, the SSE decreased twelfth folds when relaxation was taken into consideration. These results further confirm the utility of the proposed throughput method for estimating the solid fraction of ribbons.

Insensitivity of compaction properties of brittle granules to size enlargement by roller compaction.

Pharmaceutical granules prepared by roller compaction often exhibit significant loss of tabletability, that is, reduction in tensile strength, when compared to virgin powder. This may be attributed to granule size enlargement for highly plastic materials, for example, microcrystalline cellulose. The sensitivity of powder compaction properties on granule size variations impacts the robustness of the dry granulation process. We hypothesize that such sensitivity of compaction properties on granule size is minimum for brittle materials because extensive fracture of brittle granules during compaction minimizes differences in initial granule size. We tested the hypothesis using three common brittle excipients. Results show that the fine (44-106 microm), medium (106-250 microm), and coarse (250-500 microm) granules exhibit essentially identical tabletability below a certain critical compaction pressure, 100, 140, and 100 MPa for spray-dried lactose monohydrate, anhydrous dibasic calcium phosphate, and mannitol, respectively. Above respective critical pressure, tabletability lines diverge with smaller granules exhibiting slightly higher tablet tensile strength at identical compaction conditions. Overall, tabletability of brittle granules is insensitive to granule size enlargement. The results provide a scientific basis to the common practice of incorporating brittle filler to a typical tablet formulation processed by roller compaction granulation.