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.

The impacts of roller compaction on the quality attributes of simultaneously compressed micro and minitablets.

The challenges of developing good quality low dose minitablets was assessed by systematically studying the effects of ibuprofen (IBU, a model compound) particle sizes (6-58 µm D50) and concentrations (0.1-3 %w/w), roller compaction forces (3-7 kN/cm), and the minitablet sizes (1.2, 1.5 and 2 mm diameter). A novel compression approach, where all three minitablet sizes were simultaneously produced in a single compression run was used. Roller compacted ribbons, granules, minitablets were characterized for physico-mechanical properties and minitablets were also characterized for stratified content uniformity and weight uniformity. The results showed that roll force was the more dominant factor to ribbon solid fraction or tensile strength and granule size enlargement. Minitablets obtained from the granules had good weight uniformity; all but one batch met the criteria. The precise control of tooling lengths across the various sizes was found profoundly important for achieving expected weights, solid fraction, and tensile strength of the simultaneously produced minitablets. The roller compaction process considerably improved the CU variability of the minitablets as compared to the direct compression process. Smaller particle size and higher concentration of IBU, increased roller compaction force, and larger minitablet size improved the potency and content uniformity; however, only the minitablet size was a statistically significant factor in this study. As a product strategic design criterion, a threshold of 25 minitablets in a dosage unit would ensure robust downstream filling and weight verification operations as well as dose accuracy and uniformity (would pass stage 1 criteria). This study results demonstrated feasibility of the novel simultaneous compression approach and the roller compaction process in developing good quality minitablets.

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.

A Novel Use of Nanocrystalline Suspensions to Develop Sub-Microgram Dose Micro-Tablets.

Developing solid oral drug products with good content uniformity (CU) at low doses is challenging; this challenge further aggravates when the tablet size decreases from a conventional tablet to a micro/mini-tablet (1.2-3 mm diameter). To alleviate the CU issues, we present a novel use of nanocrystalline suspension combined with high shear wet granulation for the first time. In this approach, nanomilled drug in the form of nanocrystalline suspension is sprayed onto the powder bed to ensure uniform distribution. The resulting granules had adequate particle size distribution and flow characteristics to enable manufacturing of micro-tablets with good weight uniformity and tensile strength. Nanomilled drug resulted in excellent content uniformity among individual micro-tablets even at a dose strength as low as 0.16 mcg, whereas micronized drug resulted in unacceptable CU even at 5x higher dose strength (0.8 mcg). Besides, the use of nanomilled drug has enhanced the dosing flexibility of micro-tablets and showed superior dissolution performance in comparison with micronized drug with no impact of storage conditions (40 °C/75%RH for six months) on their dissolution performance. The proposed approach is simple and can be easily incorporated into traditional high shear wet granulation process to develop sub-microgram dose solid oral drug products.

Pharmaceutical amorphous solid dispersion: A review of manufacturing strategies.

Amorphous solid dispersions (ASDs) are popular for enhancing the solubility and bioavailability of poorly water-soluble drugs. Various approaches have been employed to produce ASDs and novel techniques are emerging. This review provides an updated overview of manufacturing techniques for preparing ASDs. As physical stability is a critical quality attribute for ASD, the impact of formulation, equipment, and process variables, together with the downstream processing on physical stability of ASDs have been discussed. Selection strategies are proposed to identify suitable manufacturing methods, which may aid in the development of ASDs with satisfactory physical stability.

Pediatric formulation development - Challenges of today and strategies for tomorrow: Summary report from M-CERSI workshop 2019.

A workshop on "Pediatric Formulation Development: Challenges of Today and Strategies for Tomorrow" was organized jointly by the University of Maryland's Center of Excellence in Regulatory Science and Innovation (M-CERSI), the U.S. Food and Drug Administration (FDA) and the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) Drug Product Pediatric Working Group (PWG). This multi-disciplinary, pediatric focused workshop was held over a two-day period (18-19 Jun 2019) and consisted of participants from industry, regulatory agencies, academia and other organizations from both US and Europe. The workshop consisted of sequential sessions on formulation, analytical, clinical, and regulatory and industry lessons learned and future landscape. Each session began with a series of short framing presentations, followed by facilitated breakout sessions and panel discussion. The formulation session was dedicated to three main topics pertaining to drug product acceptability, excipients in pediatrics and oral administration device considerations. The analytical session discussed key considerations for dosing vehicle selection and analytical strategies for testing of different dosage forms, specifically mini-tablets (multiparticulates). The clinical session highlighted the influence of pediatric pharmacokinetics prediction on formulation design, pediatric drug development strategies and clinical considerations to support pediatric formulation design. The regulatory and industry lessons learned and future landscape session explored the regional differences that exist in regulatory expectations, requirements for pediatric formulation development, and key patient-centric factors to consider when developing novel pediatric formulations. This session also discussed potential collaboration opportunities and tools for pediatric formulation development. This manuscript summarizes the key discussions and outcomes of all the sessions in the workshop with a broadened review and discussion of the topics that were covered.

Decoding the small size challenges of mini-tablets for enhanced dose flexibility and micro-dosing.

Mini-tablets are an age appropriate dosage form for oral administration to pediatric and geriatric patients, either as individual mini-tablets or as composite dosage units. Smaller size mini-tablets than the commonly used 2 mm or larger size would offer more tailored micro-dose delivery of investigational drugs. This work demonstrated drug substance particle size, drug loading and mini-tablet size ranges to achieve acceptable quality attributes of mini-tablets. A platform formulation with 60, 80, and 100 µm (particle size D6,3) ibuprofen at 3, 14, and 25% loadings were directly compressed into 1.2, 1.5, 2, and 2.5 mm diameter mini-tablets. With an enhanced weight control approach, all the mini-tablet batches except the 1.2 mm diameter mini-tablets with 100 µm ibuprofen at 3% loading would achieve acceptable content uniformity as individual mini-tablets (USP <905> L2 criteria) and as composite dosage units of five or more mini-tablets (USP <905> L1 criteria). A dissolution method was developed and successfully utilized to evaluate the formulations herein. Small size mini-tablets, small ibuprofen particle size, and low dose (or low ibuprofen loading) enhanced the dissolution performance. In addition, hypothetical scenarios of potential dose flexibility, dose range, dose titration, and excipient burden were discussed. The results of this study provide guidance for development of smaller size mini-tablets that enable dosing as a single or composite dosage unit, reduce excipient burden and leverage dispensing technology to achieve enhanced dosing flexibility and micro-dosing.

Development of low dose micro-tablets by high shear wet granulation process.

Low dose micro-tablets with acceptable quality attributes, specifically content uniformity (CU), would not only enhance the dose flexibility in the clinic, but also decrease excipient burden in pediatric population. Considering the CU challenges associated with directly compressed low dose micro-tablets, in this study, high shear wet granulation (HSWG) process was evaluated to manufacture micro-tablets with reduced CU variability. The impact of active pharmaceutical ingredient (API) particle size (D90 - 18-180 µm) and loading (0.67-16.67% w/w) on the critical quality attributes of micro-tablets (1.2 and 1.5 mm) like weight variability, CU, and dissolution were evaluated. Experimental results showed that final blends with flow function coefficient (ffc) ≥ 5.4 or Hausner ratio (HR) ≤ 1.43 facilitated robust compression of micro-tablets. With enhanced weight control, all the batches except the 1.2 mm micro-tablets and 2.0 mm micro-tablets with 0.67% w/w API loading and coarse API particle size (D90 - 180 µm) resulted in CU variability that meets the USP <905> CU acceptance criteria for individual micro-tablets. Apart from the above mentioned 1.2 mm micro-tablets, all the batches meet the USP <905> CU acceptance criteria for composites of 10 or more micro-tablets. Precise delivery of micro-tablets manufactured in the current study would allow dose titration in the increments of 11 mcg. The API particle size and loading impacted the in-vitro dissolution performance of micro-tablets with smaller API particle size and lower loading resulting in faster release profiles. This study provides a framework for developing low dose micro-tablets with acceptable quality attributes using HSWG process for micro-dosing, enhanced dose flexibility, and decreased excipient burden.

Assessment of Intragranular and Extragranular Fracture in the Development of Tablet Tensile Strength.

When a tablet is compacted from deformable granules and then broken, the fracture plane may cleave granules in 2 (intragranular fracture) or separate neighboring granules (extragranular fracture). In this study, a novel method was developed to quantify the extent of intragranular versus extragranular fracture by compacting tablets from multicolored ideal granules and evaluating fracture surfaces. The proportions of intragranular and extragranular fracture were quantified and modeled in light of a new metric; the deformation potential, Δ, reflecting the solid fraction increase as an initial granule bed is compressed into a final tablet. Results show that a measurable tablet strength is achieved at Δ > 0.18, but intragranular fracture is not observed until Δ > 0.21. At very large Δ, tablets experience almost exclusively intragranular fracture, yet the tablet tensile strength is considerably lower than that of a tablet compacted from raw powders versus precompacted granules. Thus, secondary compaction of granules appears to weaken the granule matrix, leading to reduced tablet tensile strength even in the presence of strong extragranular bonding.

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.