(M0930-11-71) Characterization of Compression Behavior of Co-processed Excipient for Production of Orally Dispersible Tablets and of Their Blends with Active Ingredient

Purpose: Orally Dispersable Tablets (ODTs) are designed to disintegrate or dissolve rapidly in the mouth on contact with saliva, thus eliminating the need to chew the tablet, swallow an intact tablet, or take the tablet with liquids Therefore ODTs can allow to improve treatment compliance and comfort of patients suffering dysphagia or other kinds of impaired swallowing [1]. Co-processed excipients suitable for compression into fast disintegrating tablets (CPE-ODT) are available on the market from several manufacturers. Usually they comprise a soluble filler and a superdisintegrant, possibly combined with other excipients functional to the applied co-processing technique (i.e. granulation, spray drying) [2]. CPE-ODT can be directly blended with active ingredient and lubricant and compressed into tablets, resulting in cost and time efficient development and manufacturing process. Investigation of relationships among compaction stress (i.e. pressure), compacts solid fraction or porosity and compacts mechanical strength (i.e. tensile strength) is fundamental to optimize and speed-up tablets composition screening and tableting process development [3]. Reaching a good balance between strength of inter-particles bonding and porosity is particularly important for ODTs that must quickly disintegrate maintaining mechanical resistance suitable for downstream operations (i.e. packaging) and handling. This work aimed to establish a general (pre)formulation screening method based on generation of compressibility, compactibility and tablettability profiles of selected CPE-ODTs blended with increasing amounts of target drug. These data should provide useful indication about drug load impact on compression behavior and on key properties (friability, disintegration time) of the obtained ODTs.

Methods: The CPE-ODTs selected for this work were: Ludiflash^® (BASF, D), Pharmaburst^® 500 (SPI Pharma, F), F-Melt^® Type C (Fuji Health Science, J), Smart EX^® (ShinEtsu, J). Ludipress (BASF, D) CPE was selected as non-ODT comparison reference. All these materials were kindly provided by the manufacturers. Target drug was niacin fine powder with d₅₀=20 µm as per supplier CoA (Lonza Europe, CH). Blends of CPE-ODTs and niacin listed in Table 1 have been prepared in a free fall blender (MB015, Pharmatech, England) equipped with 1 liter bin. Batch size was 250 g. Pre-blending of all components other than lubricant was conducted at 15 rpm for 15 minutes. Blending with lubricant was conducted at 15 rpm for 3 minutes. True density (Accupyc 1330 pycnometer), angle of repose and mass flow were measured for niacin and for all the prepared blends (Pharmatest PTG-1). Blends were compacted using an instrumented single punch tablet press (EK0, Korsch, D) equipped with one round flat faced punch of 11.28 mm diameter. Target weight was 450 mg ± 5%. Fifteen tablets were prepared at each compaction pressure: 40, 80, 120 and 160 MPa. Each tablet was characterized for weight (analytical balance Sartorius Secura125-1s), thickness (digital caliper 0.01 mm, Mitutoyo Ltd, J), hardness (hardness tester M8-Dr.Schleuniger Pharmatron), friability (USP-NF tester Erweka-TAR) and disintegration time (USP-NF Erweka ZT-3). Tensile strength, solid fraction and porosity values were derived from the measured properties of blends and tablets [3-5]. Heckel (HK) and Ryshkewitch-Duckworth (RD) equations [3-5] were used to fit experimental data and obtain respectively mean yield pressure (P_y), indicator of blend compressibility, and slope of RD linear regression (k_r), indicator of blend compactibility. Slope of linear regression of tensile strength versus compaction force (TA) values was used as tabletability indicator (k_a) [3-5].

Results: The correlation coefficients (R, Table 2) of the compressibility, compactibility and tabletability regressions range from 0.950 to 0.999 indicating reliability of the linear fitting and of the derived parameters for all the tested materials. The analysis of regression parameters (Table 2) suggest that Ludiflash^®, F-Melt^® and SmartEx^® compressibility is significantly higher (P_y values difference of 40-50 MPa [6]) than that of Pharmaburst^® and Ludipress^®; whilst F-Melt^® C showed the highest value of k_a, significantly different (about 100 MPa) than that of other tested CPEs, suggesting the best tabletability. According with values of k_r (ranging between 0.1150 to 0.1222) the evaluated CPE-ODTs have comparable comapctibility. The value of porosity at similar compaction pressure are comparable for all the CPE-ODTs, and reflect very fast disintegration time ranging from 4-8 seconds to 60 seconds with increase of pressure from about 40 to about 170 MPa. On the other hand friability values below the Pharmacopoeial standard of 1% were obtained at low compaction pressure (80 MPa) for Ludiflash^® and F.Melt^® C only; other tested CPEs required 160 MPa or more to comply with that limit. Niacin seems to impact negatively the compression performance and to increase disintegration time and friability when blended with CPE-ODTSs, with a very significant effect at 50% drug load, and minor impact at 10% drug load.

Conclusion: The applied screening approach allowed to point out differences of blends compression depending on CPE-ODT type and on drug load. These differences could explain the observed changes of compacts porosity, tensile strength, friability and disintegration time values. This approach will be further evaluated in new experimental works with other target drugs.

References: [1] CDER, ”Guidance for Industry Orally Disintegrating Tablets”, December 2008
[2] Bowles BJ et al.,” Co-Processed Excipients for Dispersible Tablets-Part 1: Manufacturability”, AAPS PharmSciTech. 2018 Aug;19(6):2598-2609
[3] Katz JM, Buckner IS ”Full Out-of-Die Compressibility and Compactibility Profiles From Two Tablets”, J. Pharm. Sci 2017 Mar;106(3):843-849
[4] USP 42 – monograph Tablets compression characterization
[5] Yu Y, Zaho L et al. ”A model to simultaneously evaluate the compressibility and compactibility of a powder based on the compression ratio”, Int. J. Pharm. 577 (2020): 119023
[6] Šanti M, Ilić I et al. ”A compressibility and compactibility study of real tableting mixtures: the effect of granule particle size”, Acta Pharm. 62(2012): 325-340