Lamivudine (LMD), an enantiomer of 2\'-deoxy-3\'-thiacytidine, plays a crucial role in combatting HIV-1 and managing hepatitis B virus infections. Despite its effectiveness, challenges arise from its difficult flowability and tendency to agglomerate during storage, necessitating a granulation step before tablet compression, as direct compression has proven ineffective. This study aimed to optimize Lamivudine spherical agglomerates using response surface methodology, delving into the intricate relationship between design factors (concentration of tween, span, and acetone) and experimental outcomes (yield and particle size) through central composite design. Analysis of variance (ANOVA) was employed for optimization, with the Quasi-emulsion solvent-diffusion (QESD) crystallization technique utilized for the checkpoint batch. This technique, involving a single solvent and antisolvent with surfactants, showcased remarkable enhancements in flowability and reduced storage agglomeration. The impact of various surfactants [Hydroxy Propyl Methyl Cellulose (HPMC), polysorbate 80, and sorbitane monooleate] on particle morphology, flowability, and storage agglomeration during crystallization was thoroughly assessed. While achieving direct compression into tablets, the porous structure of LMD agglomerates presented challenges in tablet press production speeds, prompting adjustments such as reducing punch speed or implementing a precompression step. Positive outcomes were realized for disintegration and in vitro drug release in comparison to direct compression and wet granulation methods. In conclusion, the QESD crystallization technique successfully yielded hollow, spherical LMD agglomerates with enhanced properties, representing a significant milestone in pharmaceutical formulation.

During recent years there have been shortages of certain drugs due to problems in raw material supply. These are often related to active ingredients but could also affect excipients. Lactose is one of the most used excipients in tableting and comes in two anomeric and several solid-state forms. The aim of this study was to utilize lactose from a dairy side-stream and compare it against a commercial reference in direct compression. This would be a sustainable option and would secure domestic availability during crises. Two types of lactose, spray-dried and freeze-dried, were evaluated. Lactose was mixed with microcrystalline cellulose in different ratios together with lubricant and glidant, and flowability and tabletability of the formulations was characterized. The fully amorphous and small particle-sized spray-dried lactose flowed inadequately but exhibited good tabletability. The larger particle-sized, freeze-dried lactose exhibited sufficient flow and better tabletability than the commercial reference. However, disintegration and drug release were slower when using the investigational lactose formulations. This was most likely due to remaining milk proteins, especially caseins, in the lactose. Overall, the investigational lactose provides promise for the use of such a side-stream product during crisis situations but enhancing their properties and/or purity would be needed.

Mini-tablets (MTs) with losartan potassium were developed to treat the rare disease Epidermolysis Bullosa. The focus was placed on transfer and scale-up of a direct compressible formulation from the compaction simulator STYL\'One Evo (CS) to the rotary tablet press Korsch XM 12 (RP). Transfer of tabletability and compactibility profiles from CS to RP did not show good agreement, e.g. at a tableting pressure of 125 MPa mean tensile strengths (TS) of 4 MPa on CS and 1-1.5 MPa on RP were reached. These results highlight the impact of the feed frame on final product qualities depending on process and material factors. In the scale-up studies the critical quality attributes (CQAs) mass variation, content uniformity, TS and disintegration time were investigated. After an appropriate run-up time, most CQAs reached a plateau, after reaching a balance between influx, efflux and distribution of lubricant in the feed frame. TS values of 1-2 MPa, disintegration times of max. 50 s, mass variation of 0.9-2.2 % (CV) and acceptance values below 15.0 were reached depending on chosen process parameters.

Solid dosage forms based on hypromellose (HPMC) with prolonged/extended drug release are very important from the research and industrial viewpoint. In the present research, the influence of selected excipients on carvedilol release performance from HPMC-based matrix tablets was studied. A comprehensive group of selected excipients was used within the same experimental setup, including different grades of excipients. Compression mixtures were directly compressed using constant compression speed and main compression force. LOESS modelling was used for a detailed comparison of carvedilol release profiles via estimating burst release, lag time, and times at which a certain % of carvedilol was released from the tablets. The overall similarity between obtained carvedilol release profiles was estimated using the bootstrapped similarity factor (f2). In the group of water-soluble carvedilol release modifying excipients, which produced relatively fast carvedilol release profiles, POLYOXᵀᴹ WSR N-80 and Polyglykol® 8000 P demonstrated the best carvedilol release control, and in the group of water-insoluble carvedilol release modifying excipients, which produced relatively slow carvedilol release profiles, AVICEL® PH-102 and AVICEL® PH-200 performed best.

The maximal amount of drug contained in a minitablet is limited. To reduce the total number of minitablets in a single dose, high drug load minitablets can be prepared from high drug load feed powders by various pharmaceutical processing techniques. Few researchers have however examined the influence of pharmaceutical processing techniques on the properties of high drug load feed powders, and consequently the manufacturability of high drug load minitablets. In this study, silicification of the high drug load physical mix feed powders alone did not yield satisfactory quality attributes and compaction parameters to produce good quality minitablets. The abrasive nature of fumed silica increased ejection force and damage to the compaction tools. Granulation of fine paracetamol powder was crucial for the preparation of good quality high drug load minitablets. The diminutive granules had superior powder packing and flow properties for homogenous and consistent filling of the small die cavities when preparing minitablets. Compared to the physical mix feed powders for direct compression, the granules which possessed higher plasticity, lower rearrangement and elastic energies, yielded better quality minitablets with high tensile strength and rapid disintegration time. High shear granulation demonstrated greater process robustness than fluid bed granulation, with less discernment on the quality attributes of feed powder. It could proceed without fumed silica, with the high shear forces reducing interparticulate cohesivity. An in-depth understanding on the properties of high drug load feed powders with inherently poor compactability and poor flowability is important for the manufacturability of high drug load minitablets.

A co-processed, rice starch-based excipient (CS), previously developed and shown to exhibit good pharmaceutical properties, is investigated as an all-in-one excipient for direct compression (DC). An SeDeM-ODT expert system is applied to evaluate the formulation containing CS, in comparison with those containing the physical mixture and the commercial DC excipients. The results revealed that CS showed acceptable values in all six incidence factors of the SeDeM-ODT diagram. In addition, the comprehensive indices (IGC and IGCB) were higher than 5.0, which indicated that CS could be compressed with DC technique without additional blending with a disintegrant in tablet formulation. The formulation study suggested that CS can be diluted up to 60% in the formulation to compensate for unsatisfactory properties of paracetamol. At this percentage, CS-containing tablets exhibited narrow weight variation (1.5%), low friability (0.43%), acceptable drug content (98%), and rapid disintegration (10 s). The dissolution profile of CS displayed that more than 80% of the drug content was released within 2 min. The functionality of CS was comparable to that of high functionality excipient composite (HFEC), whereas other excipients were unsuccessful in formulating the tablets. These results indicated that CS was a suitable all-in-one excipient for application in DC of tablets.

Continuous manufacturing (CM) has emerged in the pharmaceutical industry as a paradigm shift with significant advantages related to cost, efficiency, flexibility, and higher assurance of quality. The inherent differences from batch processes justify examining the CM control strategy more holistically. This article describes the current thinking for the control and implementation of CM, using the example of a direct compression process and taking into consideration the ICH Q10 definition of \"state of control\" and process validation requirements. Statistical process control using control charts, sources of variation, process capability, and process performance is explained as a useful concept that can help assess the impact of variation within a batch and indicates if a process is in state of control. The potential for time-variant nature of startup and shutdown with CM is discussed to assure product quality while minimizing waste as well as different options for detection and isolation of non-conforming materials due to process upsets. While different levels of control are possible with CM, an appropriate balance between process control and end product testing is needed depending on the level of process understanding at the different stages of development from the production of clinical supplies through commercialization.

OBJECTIVE: The aim of this article is to compare the gravitational powder blend loading method to the tablet press and manual loading in terms of their influence on tablets\' critical quality attributes (CQA).
CONCLUSIONS: The results of the study can be of practical relevance to the pharmaceutical industry in the area of direct compression of low-dose formulations, which could be prone to content uniformity (CU) issues.
METHODS: In the preliminary study, particle size distribution (PSD) and surface energy of raw materials were determined using laser diffraction method and inverse gas chromatography, respectively. For trials purpose, a formulation containing two pharmaceutical ingredients (APIs) was used. Tablet samples were collected during the compression progress to analyze their CQAs, namely assay and CU.
RESULTS: Results obtained during trials indicate that tested direct compression powder blend is sensitive to applied powder handling method. Mild increase in both APIs content was observed during manual scooping. Gravitational approach (based on discharge into the drum) resulted in a decrease in CU, which is connected to a more pronounced assay increase at the end of tableting than in the case of manual loading.
CONCLUSIONS: The correct design of blend transfer over single unit processes is an important issue and should be investigated during the development phase since it may influence the final product CQAs. The manual scooping method, although simplistic, can be a temporary solution to improve the results of API\'s content and uniformity when compared to industrial gravitational transfer.

OBJECTIVE: Dispersible tablets are proposed by the World Health Organization as the preferred paediatric formulation. It was hypothesised that tablets made from a powdered milk-base that disperse in water to form suspensions resembling milk might be a useful platform to improve acceptability in children.
METHODS: Milk-based dispersible tablets containing various types of powdered milk and infant formulae were formulated. The influence of milk type and content on placebo tablet properties was investigated using a design-of-experiments approach. Responses measured included friability, crushing strength and disintegration time. Additionally, the influence of compression force on the tablet properties of a model formulation was studied by compaction simulation.
RESULTS: Disintegration times increased as milk content increased. Compaction simulation studies showed that compression force influenced disintegration time. These results suggest that the milk content, rather than type, and compression force were the most important determinants of disintegration.
CONCLUSIONS: Up to 30% milk could be incorporated to produce 200 mg 10-mm flat-faced placebo tablets by direct compression disintegrating within 3 min in 5-10 ml of water, which is a realistic administration volume in children. The platform could accommodate 30% of a model active pharmaceutical ingredient (caffeine citrate).