Current State of Minitablet Product Design: A Review.

Interest in minitablets (MTs) has grown exponentially over the last 20 years and especially the last decade, as evidenced by the number of publications cited in Scopus and PubMed. MTs offer significant opportunities for personalized medicine, dose titration and flexible dosing, taste masking, and customizing drug delivery systems. Advances in specialized MT tooling, manufacturing, and characterization instrumentation have overcome many of the earlier development issues. Breakthrough MT swallowability, acceptability, and palatability research have challenged the long-standing idea that only liquids are acceptable dosage forms for infants and young children. MTs have been shown to be a highly acceptable dosage form for infants, small children, and geriatric patients who have difficulty swallowing. This review discusses the current state of MT applications, acceptability in pediatric and geriatric populations, medication adherence, manufacturing processes such as tableting and coating, running powder and tablet characterization, packaging and MT dispensing, and regulatory considerations.

Effect of Manufacturing Process on the Retention of Abuse-Deterrent Properties of PEO-Matrix Tablets.

Polyethylene oxide (PEO) is a widely used polymer in the development of abuse-deterrent oral formulations. Different manufacturing processes including direct compression (DC) followed by sintering, wet granulation (WG) followed by compression and sintering, and hot melt extrusion (HME) can be used to manufacture abuse-deterrent oral drug products. Three different manufacturing processes (DC, WG, HME) were evaluated to test the retention of their abuse-deterrent features following attempts to grind the tablets or extrudates. In vitro drug release studies were conducted on 10% and 32% drug-loaded tablets/extrudates prepared using these manufacturing methods, and the release profiles from all formulations showed good extended-release properties. Drug content analysis on the granules obtained from tablets prepared by direct compression showed non-uniform drug distribution where an unexpectedly high drug content was present in the smallest size (< 250 µm) granules, sizes which are likely to be inhaled by abusers. Granules from tablets prepared by wet granulation showed improved drug distribution across all granule sizes formed after grinding. Drug content testing on the granules obtained from extrudates prepared using hot melt extrusion showed excellent drug content uniformity along with sufficient strength to resist grinding into smaller particles. The retention of the abuse-deterrent properties of a dosage form following attempts to extract or abuse the drug is an important product characteristic, and the product design, formulation components, and manufacturing processes can all play critical roles in the retention of the desired abuse-deterrent properties.

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.

Use of Drug Release Testing to Evaluate the Retention of Abuse-Deterrent Properties of Polyethylene Oxide Matrix Tablets.

Abuse-deterrent formulations (ADFs) using physical/chemical barrier approaches limit abuse by providing resistance to dosage form manipulation to limit drug extraction or altered release. Standardizing in vitro testing methods to assess the resistance to manipulation presents a number of challenges, including the variation in particle sizes resulting from the use of various tools to alter the tablet matrix (e.g., grinding, chipping, crushing). A prototype, direct-compression ADF using a sintered polyethylene oxide (PEO) matrix containing dextromethorphan, an enantiomeric form of the opioid, levorphanol, was developed to evaluate testing methodologies for retention of abuse-deterrent properties following dosage form tampering. Sintered PEO tablets were manipulated by grinding, and drug content and release were evaluated for the recovered granules. Drug content analysis revealed that higher amounts of drug were contained in the smaller size granules (< 250 µm, 190% of the theoretical amount) compared with the larger particles (> 250 µm, 55-75% of theoretical amount). Release testing was performed on various size granule fractions (> 850 µm, 500-850 µm, 250-500 µm, and < 250 µm) using USP type I (basket), type II (paddle), and type IV (flow-through) apparatus. The USP type I and type II apparatus gave highly variable release results with poor discrimination among the release rates from different size granules. The observed sticking of the hydrated granules to the baskets and paddles, agglomeration of hydrated granules within the baskets/vessels, and ongoing PEO hydration with subsequent gel formation further altered the particle size and impacted the rate of drug release. The use of a flow-through apparatus (USP type IV) resulted in improved discrimination of drug release from different size granules with less variability due to better dispersion of granules (minimal sticking and aggregation). Drug release profiles from the USP type IV apparatus showed that the larger size granules (> 500 µm) offered continued resistance to drug release following tablet manipulation, but the smaller size granules (< 500 µm) provided rapid drug release that was unhindered by the hydrated granule matrix. Since < 500-µm size particles are preferred for nasal abuse, improved direct-compression ADF formulations should minimize the formation of these smaller-sized particles following tampering to maintain the product's abuse-deterrent features.

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.

Role of wetting agents and disintegrants in development of danazol nanocrystalline tablets.

Poor wetting and/or particle aggregation are the shortcomings of the dried nanocrystalline suspensions, which subsequently might hinder the superior dissolution performance of the nano-crystalline suspensions. The objective of this study was to evaluate the effect of wetting agents and disintegrants on the dissolution performance of dried nanocrystals of an active pharmaceutical ingredient (API) with poor wetting property. Danazol, a BCS Class II compound with high LogP and low polar surface area, was chosen as a model compound for this study. Danazol nanocrystalline suspension was prepared by wet-media milling and converted into powder via spray granulation either with mannitol or microcrystalline cellulose as carriers at a drug: carrier ratio of 1:9 w/w. Danazol nanocrystalline suspension showed a superior dissolution performance compared to an un-milled danazol suspension. Dried danazol nanocrystals suffered from poor wetting leading to hindered dissolution performance i.e. ~ 40% and ~ 15% drug dissolution within 15 min for the mannitol and microcrystalline cellulose-based granules, respectively. Addition of a lipophilic surfactant (i.e. docusate sodium) at a surfactant: drug ratio of 0.015: 1 w/w during granulation helped in retaining the superior drug dissolution rates i.e. more than 80% drug dissolution within 15 min for mannitol-based granules by enhancing the wettability of dried danazol nanocrystals when compared to a hydrophilic surfactant (i.e. poloxamer 188) or disintegrant (i.e. sodium starch glycolate or croscarmellose sodium). The fast-dissolving mannitol-based granules containing danazol nanocrystals and docusate sodium were compressed into a tablet dosage form. The tablets containing danazol nanocrystals with docusate sodium showed a superior dissolution performance compared to a tablet containing un-milled danazol with docusate sodium.

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.

Polyethylene Oxide (PEO) Molecular Weight Effects on Abuse-Deterrent Properties of Matrix Tablets.

While polyethylene oxide (PEO)-based matrix tablets are frequently used as abuse-deterrent dosage forms, there is limited information available regarding how the selection of formulation components and manufacturing processes affect the resulting abuse-deterrent properties. The objective of the current study was to evaluate the effects of formulation and process variables on the abuse-deterrent features of PEO-containing tablets. Directly compressed tablets were prepared using three different PEO molecular weights (100,000; 900,000; and 5,000,000). As anticipated, sintering/thermal treatment above the melting point of PEO was crucial to impart crush-resistant features (tablet hardness > 500 N). In addition to the sintering temperature, the weight fraction of PEO in the tablets affected their mechanical strength, and at least 50% w/w PEO was required to impart the desired crush-resistant features. In addition, the formulation and process variables also impacted syringeability and injectability of the PEO gels formed when the tablets were hydrated to simulate attempted drug extraction. High molecular weight PEO (900,000 and 5,000,000) produced gels more resistant to syringeability and injectability compared to low molecular weight PEO (100,000). Sintering above the polymer melting point decreased PEO crystallinity after cooling, and longer sintering times resulted in PEO degradation producing lower viscosity gels with reduced resistance to syringeability and injectability. Although sintering above the melting point of PEO imparts optimal mechanical strength to the tablets, prolonged sintering durations negatively impact polymer stability and alter the resulting abuse-deterrent features of the PEO-based tablet formulations.

Human volunteer, in vitro, and molecular level evaluation of an optimized taste-masked isoniazid-chitosan spray-dried microparticle matrix.

For the first time, isoniazid (INH) bitterness value, threshold, and sensitivity (low, moderate, high, and extremely high) was determined in six human volunteers. INH demonstrated a large range in bitterness sensitivity. The current work demonstrates the design of a taste-masked isoniazid (INH)-loaded chitosan microspheres (INH-LCM) using an ionic-gelation and spray drying technique. A 24 full factorial design with three center points was employed to optimize and study the independent variables (chitosan concentration, sodium tripolyphosphate (TPP)-volume, feed rate, and air inlet temperature) effects on the critical quality attributes (percent yield [PY] and entrapment efficiency [EE]). Statistically significant models were developed for PY (p = 0.0357; adjusted R2 = 0.6078) and EE (p = 0.0190; adjusted R2 = 0.6713). A multicriteria prediction profiler was utilized to determine the optimum formulation and process parameters. Two verification batches confirmed excellent predictability and lot-to-lot consistency. In vitro dissolution was used to evaluate the taste masking ability of INH-LCM. The in vitro dissolution test of the optimized INH-LCM suggested that taste masking would be accomplished for the "low" and "moderate" bitterness taste sensitivity groups. Further in vitro and human volunteer taste panel studies with INH-LCM are required for better understand the potential taste masking capability for the "high" and "extremely high" bitterness taste sensitivity groups. The in vitro dissolution method and FTIR data analysis support that TPP crosslinked chitosan may provide taste masking by two mechanisms: (1) acts as a physical barrier and delays INH dissolution; and (2) provides a chemical barrier by forming hydrogen bonds between INH's bitter tasting amino group and chitosan.

Downstream processing of irbesartan nanocrystalline suspension and mini-tablet development - Part II.

The objectives of this study were to evaluate the impact of formulation variables on the drying of nanocrystalline suspensions either via bead layering or spray granulation and develop mini-tablets from the dried nanocrystalline powders. Irbesartan (crystalline Form B), a poorly soluble drug substance was chosen as a model compound. An optimized irbesartan nanocrystalline suspension with a mean particle size of 300 nm was utilized for the downstream processing. Irbesartan nanocrystalline suspension was dried either by layering onto the microcrystalline cellulose beads (i.e. 200 or 500 µm) or by granulation (mannitol or microcrystalline cellulose as substrates) at two different drug loadings (i.e. 10% or 30% w/w). Smaller size beads layered with nanocrystals resulted in faster dissolution profiles compared to larger size beads at both the studied drug loadings (i.e. 10 and 30% w/w). Mannitol granules containing irbesartan nanocrystals resulted in faster dissolution profiles compared to microcrystalline cellulose granules. Microcrystalline cellulose beads and mannitol granules containing irbesartan nanocrystals (i.e. 30% w/w drug loading) were further compressed into mini-tablets. Mini-tablets retained fast drug dissolution characteristics of the dried powders. The results from this study indicated that the spray granulation is a superior drying approach compared to bead layering for drying of irbesartan nanocrystalline suspension and mini-tablet development.

Formulation and performance of Irbesartan nanocrystalline suspension and granulated or bead-layered dried powders - Part I.

Nanocrystalline suspensions offer a promising approach to improve the dissolution rate of BCS Class II/IV drugs and hence oral bioavailability. Irbesartan (crystalline Form B), a poorly soluble drug substance was chosen as a model compound for the study. The objectives of the study were to formulate Irbesartan nanocrystalline suspension via media milling, study the effects of process and formulation variables on particle size reduction, and evaluate bead layering or spray granulation as drying processes. A Design of Experiment approach was utilized to understand the impact of formulation variables on particle size reduction via media milling. Drug concentration and type of stabilizer were found to be significant in particle size reduction. Optimized Irbesartan nanocrystalline suspension (i.e. at 10% w/w with 1% w/w poloxamer 407) showed superior in vitro dissolution profile compared to unmilled suspension. Optimized Irbesartan nanocrystalline suspension was converted into dried powders either by bead layering (with microcrystalline cellulose) or by spray granulation (either with mannitol or microcrystalline cellulose). DSC and PXRD studies revealed that Irbesartan remained crystalline post drying. Microcrystalline cellulose beads layered with Irbesartan nanocrystals showed about 65% drug dissolution within the first 10 min of dissolution study. Mannitol granules containing Irbesartan nanocrystals were fast dissolving (i.e. >90% drug dissolution within 10 min) compared to microcrystalline cellulose granules (i.e. approx. 46% drug dissolution within 10 min). Irbesartan nanocrystalline suspension had the fastest dissolution rates (i.e. >90% drug dissolution in two minutes) followed by mannitol-based granules containing dried Irbesartan nanocrystals (i.e. >90% drug dissolution in ten minutes).

Effects of Drug-Polymer Interactions on Tablet Properties During the Development of Abuse-Deterrent Dosage Forms.

The objective of the present study is to understand the effects of drug-PEO interactions during the thermal treatment of polyethylene oxide (PEO)-based, directly compressed, abuse-deterrent formulations (ADFs). The drugs studied were dextromethorphan HBr monohydrate, ketoprofen, promethazine HCl, and anhydrous theophylline. Thermal treatment above the melting point of PEO resulted in tablets with higher crushing strength (> 500 N). It was observed that drug-PEO interactions during thermal treatment (80°C) led to solubilization of the incorporated drug. Drugs with higher solubility in the molten PEO, when added at higher weight fractions, interfered with the process of tablet densification which led to an increase in tablet dimensions and created defects in the fused matrix. These changes resulted in the formation of a more porous matrix. Thermal treatment led to a decrease in PEO crystallinity. The decreased crystallinity led to differences in the hydration and dissolution properties of the PEO. The change in dissolution properties of PEO accompanied with the dimensional and microstructural changes resulted in a greater drug release for some of the studied drugs. In conclusion, although thermal treatment above the melting point of PEO is an efficient manufacturing process in imparting crush-resistant features, drug-PEO interactions during the thermal treatment and the impact of thermal treatment on the properties of formulation components may impact tablet properties and lead to potential performance differences.

Dipalmitoylphosphatidylcholine (DPPC): Annealing Strategy to Mitigate Variability in Thermotropic and Moisture Sorption Behavior.

Dipalmitoylphosphatidylcholine (DPPC) demonstrated complex differential scanning calorimetry (DSC) thermal behavior. Transitions below 100°C showed variability in their thermotropic reversibility. An experimental design employing a DSC heat-cool-heat-cool-heat cycle and modulated DSC were used to gain insight into the DPPC's complex thermal nature. An annealing strategy was developed to reduce DPPC's thermotropic variability, moisture uptake rate, and rate variability. Samples annealed at 110°C for 5 min provided a reproducible, thermally reversible material. The annealed material also exhibited an 8-fold decrease in moisture sorption rate and a statistically significant (p = 0.0233) 100-fold decrease in water sorption rate variability compared to DPPC "as is." An optimized validated stability-indicating high performance liquid chromatography with evaporative light scattering detection method was developed and showed no change in DPPC chemical stability under the annealing treatment conditions.