Implementing novel expert systems in the design of personalized paediatric pyridoxine hydrochloride orodispersible tablets

Abstract

This research implements a computer-aided formulation development algorithm based on a novel SeDeM-ODT expert system in establishing the design space for paediatric pyridoxine hydrochloride orodispersible tablets (ODTs) using Prosolv ® ODTG2, Prosolv ® EasyTab SP, and Ludiflash ® systems. For each formulation ingredient, expert system-defined preformulation parameter values were experimentally determined according to standardized methods and then normalized to the theoretical radius range [0,10]. Expert diagrams were constructed and the quantitative performance of each ingredient was evaluated using parametric profile index (IPP), flowability (ff’), and compressibility (ffc) functions. The net direct compression capability was quantitatively expressed as the product of expert system reliability and IPP. Direct compression was conducted in an eccentric tablet press and properties were evaluated using weight, dimension, disintegration test, contact angle, tensile strength, x-ray diffraction, and Fourier-transform infrared spectroscopy. The ODTs dissolution profiles were fitted and compared using zero-order, first-order, Hixson-Crowell, and Hopfenberg models. Results of the expert diagram of pyridoxine hydrochloride indicated suboptimal normalized radii values in 8 out of 12 parameters, implying a compromised mechanical zone (ff’=3.61, ffc=2.11). By setting a target ffc for the optimized formulation mix at 5.0, the predicted proportions of the fillers to remedy the direct compression deficits of the drug were computed as 89.00%, 83.23%, and 76.62% for Prosolv ® ODTG2 (ffc=5.36), Prosolv ® EasyTab SP (ffc=5.58), and Ludiflash ® (ffc=5.88), respectively. The produced ODTs were of acceptable target quality, hence the SeDeM-ODT system was considered a reliable formulation tool for establishing the design space of this particular drug-filler systems.

Introduction

The impact of evolving regulations has necessitated special paediatric investigative plans in the formulation development of dosage forms for paediatrics [1,2]. This is necessary because the paediatric population is heterogenous with extensive variation in physiology, anatomy, and cognitive development [3]. Although in this population, the liquid dosage forms present the most suitable oral delivery system, numerous critical patient, formulation, and manufacturing considerations such as stability, cost, posology, taste-masking, and acceptability, have justified the exploration of monolithic solid dosage forms [4,5]. Administration of conventional monolithic tablets or capsules is however impractical in paediatric patients younger than 6 years as it is associated with high risks of asphyxiation, particularly in infants and toddlers, in whom buccal manipulation and swallowing of tablets may not be properly coordinated [6]. Similarly, patients with dysphagia, oropharyngeal carcinoma, stroke, or Parkinson’s disease typically present with impaired muscle tone and uncoordinated peristaltic waves to propel ingested tablets down the oesophagus [6]. Under the current European legislative frameworks, paediatric drug development must be tailored to meet the unique requirement of this population [1,2].

Orodispersible tablets (ODTs) are innovative oral drug delivery alternatives to conventional monolithic tablets that rapidly disintegrate in the oral cavity to ease swallowing, without prior mastication or supplementary water intake [4,7]. Numerous clinical studies have pointed to increased patient acceptability of the ODTs formulations [5]. Novel patented and generic technologies based on lyophilization [8,9], 3-D printing [10,11], moulding [12,13], and cotton candy [4,14] are available options for ODTs manufacturing. However, the cost implications, limited therapeutic scope, scale-up, long-term stability, dosage precision, and product fragility issues are serious concerns that impact sustainable large-scale commercial manufacturing, and also on routine clinical applications. Consequently, direct compression tablet manufacturing technology has been adapted as a cost-effective alternative for sustainable production of ODTs [15–17].

The technology utilizes fewer unit operations, equipment, and validation procedures compared to roller compaction or wet granulation technologies for manufacturing tablets [18–20]. However, this apparent simplicity holds only when the formulation ingredients satisfy the stringent multifunctional technical requirements of efficient flow, compaction, and disintegration [21]. In practice, only very few pharmaceutical solid materials are true candidates for direct compression [21,22]. Another compelling challenge in the formulation design of orodispersible systems via the direct compression route is the complexity in the selection of an appropriate design space [23]. The critical material attributes, process parameters, and the output target quality product profile relate in a non-linear and complex pattern [24]. Hence, the determination of optimized formulation parameters that would give ODTs of acceptable target quality profiles requires numerous repeated empirical trials or design of experiments, which are non-economical and time-consuming [25].

Computer-aided formulation design tools have evolved to resolve complex pharmaceutical formulation problems and reduce the time to market developed products [26,27]. The SeDeM expert system is an emerging computer-aided formulation development algorithm for the rational design of tablets via direct compression. The generated expert data informs formulation scientists and engineers of the degree to which powder formulation ingredients could produce ODTs of acceptable target quality without trial-and-error and minimal experimental runs [28,29]. The novel SeDeM-ODT expert system specifically focused on formulation design and optimization of ODTs via DC technology [16,30,31].

The novel algorithm simultaneously characterizes rheological behaviour, compressibility, dosage uniformity, stability, and orodispersibility/bucodispersibility of the powder formulation ingredients and quantitatively predicts the optimized numerical solution to compensate for compression deficits [30–32]. In addition to serving as a quality control tool for monitoring batch-to-batch reproducibility, the tool has been used to compare the direct compression performance of fillers from the same or different chemical families [33]. The expert tools have been successfully applied in the adult formulation of tablets for oral delivery of carbamazepine [34], captopril [35], ibuprofen [36], zidovudine[37], and rosuvastatin [15]. However, few studies utilized the tools in the formulation design of paediatric ODTs [38].

It is crystal clear that current European legislative frameworks on paediatric investigative plans strengthen reciprocal attention to paediatric-focused development [1,2]. Therefore, the goal of this study was to implement SeDeM-ODT expert system in the systematic design of paediatric-focused pyridoxine hydrochloride ODTs using commercially established brands of orodispersible coprocessed fillers based on Prosolv® ODTG2, Prosolv® EasyTab SP, and Ludiflash®. These coprocessed fillers are multifunctional coprocessed products designed specifically for ODTs manufacturing via direct compression. Pyridoxine hydrochloride is indicated for the management of isoniazid (INH)-induced peripheral neuropathy, INH and monomethylhydrazine poisoning, as well as vitamin B6 replenishment in deficiency states [39,40]. Thus, this study critically implements the SeDeM-ODT expert system in the design space of paediatric-centric pyridoxine hydrochloride ODTs the Prosolv®ODTG2, Prosolv® ODTG2, and Ludiflash® powder systems.

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Materials

The model active pharmaceutical ingredient pyridoxine hydrochloride was received as a donation from Vitro Health Nigeria LTD. The details of experimental directly compressible coprocessed fillers are presented in Table 5.

Table 5. Details of the experimental directly compressible coprocessed fillers.

Ilyasu SALIM1, Garba Mohammed KHALID, Abubakar Sadiq WADA, Suleiman DANLADI, Fatima Shuaibu KURFI, Mahmud Sani GWARZO, Implementing novel expert systems in the design of personalized paediatric pyridoxine hydrochloride orodispersible tablets, See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/383565187, Article in Journal of Research in Pharmacy · August 2024, DOI: 10.29228/jrp.845

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