Active Pharmaceutical Ingredient Particle Size Research Articles

Impact of active pharmaceutical ingredient variables and oleaginous base on the in vitro drug release from ophthalmic ointments: An investigation using dexamethasone as a model drug

The present study systematically investigates the impact of active pharmaceutical ingredient (API) variables and oleaginous base characteristics on the in vitro release (IVR) performance of ophthalmic ointments, utilizing dexamethasone as a model drug. The interplay between selected attributes (i.e., particle size distribution, crystallinity, and polymorphic form for API, and rheological factors for compendial-grade white petrolatum) and IVR performance was investigated. APIs from different vendors exhibited variations in crystallinity and polymorphism. Ointments containing amorphous dexamethasone presented higher release amounts/rates compared to crystalline counterparts, emphasizing the role of physical state in release kinetics. Variations in particle size of this lipophilic API (5.4 – 21.2 µm) did not appear to impact IVR performance significantly. In contrast, white petrolatum's rheological attributes, which varied substantially within USP-grade petrolatum, were found to critically affect the drug release rate and extent of the ointment. The study’s comprehensive analysis establishes a coherent connection between the quality attributes of both API and petrolatum and IVR, delineating their intricate interdependent effects on ophthalmic ointment performance. These findings provide reference to formulation design, quality control, and regulatory considerations within the pharmaceutical industry, fostering a robust foundational understanding of commonly overlooked quality attributes in ophthalmic ointments.

Analysis of Factors Related to Variation in Dissolution Profiles Estimated from Continuously Conducted Dissolution Tests of Generic Products.

The development of generic pharmaceuticals involves a bioequivalence study to ensure the therapeutic equivalence of the test formulation to the original innovative product. The formulation characteristics of generic products are expected to be maintained in the long term after approval. This study analyzed the factors contributing to the changes in the dissolution profiles of approved products during their life cycles. Cumulative data on the dissolution similarity of 1675 products of 127 ingredients tested by official laboratories in Japan were assessed according to Japanese bioequivalence guidelines with slight modifications. The products showing dissimilarities in dissolution profiles were analyzed for reporting year, therapeutic category, co-development, physical properties of the active pharmaceutical ingredient (API), and suspected reasons for dissolution change. The increase in the number of dissimilar products is related to the co-development of generic products. Although the solubility of the API was not associated with the dissolution change in the analysis of the total dissolution data, control of the API particle size is suggested to be important for drugs with poorly soluble APIs. Additionally, a risk factor for dissolution changes in the test solutions at a certain pH was the presence of acidic or basic residues. These results indicate the importance of proper development through a thorough evaluation of the formulation and process factors affecting the dissolution properties throughout the product lifecycle.

Determination of the Solid Content of Active Pharmaceutical Ingredient Powders in Suspension-Type Pharmaceutical Oral Jelly Using Time-Domain NMR.

This study determined the content of solid active pharmaceutical ingredient (API) powders dispersed in suspension-type pharmaceutical oral jellies using a low-field time-domain NMR (TD-NMR). The suspended jellies containing a designated API content were prepared and tested. Acetaminophen (APAP), indomethacin (IMC) and L-valine were used as test APIs. First, this study measured the T2 relaxation rate (the reciprocal of T2 relaxation time) by the Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence, and then evaluated whether the API content could be determined by the acquired T2 relaxation rate. The T2 relaxation rate negatively correlated with API content to a certain extent, but their correlation was not sufficient for achieving a precise determination. Subsequently, the solid-echo pulse sequence measurement was adopted for this study. We found that NMR signals corresponding to solid components strongly correlated with API content. Thus, this method achieved a precise determination of API contents in suspended jellies. In addition, this study confirmed the effect of API particle size on the T2 relaxation rate by using an L-valine-containing jelly: the T2 relaxation rate became faster when a smaller API size was incorporated into the suspended jelly, while there was no difference in terms of the NMR signals measured by solid-echo pulse sequence. From these findings, TD-NMR could be a powerful tool for evaluating the API dispersion state in suspended oral jellies.

Sensitivity of Pharmacokinetics to Differences in the Particle Size Distribution for Formulations of Locally Acting Mometasone Furoate Suspension-Based Nasal Sprays.

To assess bioequivalence of locally acting suspension-based nasal sprays, the U.S. FDA currently recommends a weight-of-evidence approach. In addition to in vitro and human pharmacokinetic (PK) studies, this includes a comparative clinical endpoint study to ensure equivalent bioavailability of the active pharmaceutical ingredient (API) at the site of action. The present study aimed to assess, within an in vitro/in vivo correlation paradigm, whether PK studies and dissolution kinetics are sensitive to differences in drug particle size for a locally acting suspension-based nasal spray product. Two investigational suspension-based nasal formulations of mometasone furoate (MF-I and MF-II; delivered dose: 180 μg) differed in API particle size and were compared in a single-center, double-blind, single-dose, randomized, two-way crossover PK study in 44 healthy subjects with oral charcoal block. Morphology-directed Raman spectroscopy yielded volume median diameters of 3.17 μm for MF-I and 5.50 μm for MF-II, and dissolution studies showed that MF-II had a slower dissolution profile than MF-I. The formulation with larger API particles (MF-II) showed a 45% smaller Cmax and 45% smaller AUC0-inf compared to those of MF-I. Systemic bioavailability of MF-I (2.20%) and MF-II (1.18%) correlated well with the dissolution kinetics, with the faster dissolving formulation yielding the higher bioavailability. This agreement between pharmacokinetics and dissolution kinetics cross-validated both methods and supported their use in assessing potential differences in slowly dissolving suspension-based nasal spray products.

A Novel Technique to Assess Drug Substance Particle Size in a Complex Inhaled Formulation

Dry powder inhalers, comprising an active pharmaceutical ingredient (API) and carrier excipients, are often used in the delivery of pulmonary drugs. The stability of the API particle size within a formulation blend is a critical attribute for aerodynamic performance but can be challenging to measure. The presence of excipients, typically at concentrations much higher than API, makes measurement by laser diffraction very difficult. This work introduces a novel laser diffraction approach that takes advantage of solubility differences between the API and excipients. The method allows insight into the understanding of drug loading effects on API particle stability of the drug product. Lower drug load formulations show better particle size stability compared with high drug load formulations, likely due to reduced cohesive interactions.

Understanding the role of magnesium stearate in lowering punch sticking propensity of drugs during compression

The sticking of active pharmaceutical ingredient (API) to the surfaces of compaction tooling, frequently referred to as punch sticking, causes costly downtime or product failures in commercial tablet manufacturing. Magnesium stearate (MgSt) is a common tablet lubricant known to ameliorate the sticking problem, even though there exist exceptions. The mechanism by which MgSt lowers punch sticking propensity (PSP) by covering API surface is sensible but not yet experimentally proven. This work was aimed at elucidating the link between PSP and surface area coverage (SAC) of tablets by MgSt, in relation to some key formulation properties and process parameters, namely MgSt concentration, API loading, API particle size, and mixing conditions. The study was conducted using two model APIs with known high PSPs, tafamidis (TAF) and ertugliflozin-pyroglutamic acid (ERT). Results showed that PSP decreases exponentially with increasing SAC by MgSt. The composition of material stuck to punch face was also explored to better understand the onset of punch sticking and the impact of possible MgSt-effected punch conditioning event.

Influence of PLGA End Groups on the Release Profile of Dexamethasone from Ocular Implants.

The present study deals with the development of dexamethasone (DM)-loaded implants using ester end-capped Resomer RG 502 poly(lactic acid-co-glycolic acid) (PLGA) (502), acid end-capped Resomer RG 502H PLGA (502H), and a 502H:502 mixture (3:1) via hot melt extrusion (HME). The prepared intravitreal implants (20 and 40% DM loaded in each PLGA) were thoroughly investigated to determine the effect of different end-capped PLGA and drug loading on the long-term release profile of DM. The implants were characterized for solid-state active pharmaceutical ingredient (APIs) using DSC and SWAXS, water uptake during stability study, the crystal size of API in the implant matrix using hot-stage polarized light microscopy, and in vitro release profile. The kinetics of PLGA release was thoroughly investigated using quantitative 1H NMR spectroscopy. The polymorph of DM crystal was found to remain unchanged after the extrusion and stability study. However, around 3 times reduction in API particle size was observed after the HME process. The morphology and content uniformity of the RT-stored samples were found to be comparable to the initial implant samples. Interestingly, the samples (mainly 502H) stored at 40 °C and 75% RH for 30 d demonstrated marked deformation and a change in content uniformity. The rate of DM release was higher in the case of 502H samples with a higher drug loading (40% w/w). Furthermore, a simple digital in vitro DM release profile derived for the formulation containing a 3:1 ratio of 502H and 502 was comparable with the experimental release profile of the respective polymer mixture formulation. The temporal development of pores and/or voids in the course of drug dissolution, evaluated using μCT, was found to be a precursor for the PLGA release. Overall, the release profile of DM was found to be dependent on the PLGA type (independent of subtle changes in the formulation mass and diameter). However, the extent of release was found to be dependent on DM loading. Thus, the present investigation led to a thorough understanding of the physicochemical properties of different end-capped PLGAs and the underlying formulation microstructure on the release profile of a crystalline water-insoluble drug, DM, from the PLGA-based implant.

The Rat Continuous Intestine Model Predicts the Impact of Particle Size and Transporters on the Oral Absorption of Glyburide

Oral drug absorption is known to be impacted by the physicochemical properties of drugs, properties of oral formulations, and physiological characteristics of the intestine. The goal of the present study was to develop a mathematical model to predict the impact of particle size, feeding time, and intestinal transporter activity on oral absorption. A previously published rat continuous intestine absorption model was extended for solid drug absorption. The impact of active pharmaceutical ingredient particle size was evaluated with glyburide (GLY) as a model drug. Two particle size suspensions of glyburide were prepared with average particle sizes of 42.7 and 4.1 μm. Each suspension was dosed as a single oral gavage to male Sprague Dawley rats, and concentration-time (C-t) profiles of glyburide were measured with liquid chromatography coupled with tandem mass spectrometry. A continuous rat intestine absorption model was extended to include drug dissolution and was used to predict the absorption kinetics of GLY depending on particle size. Additional literature datasets of rat GLY formulations with particle sizes ranging from 0.25 to 4.0 μm were used for model predictions. The model predicted reasonably well the absorption profiles of GLY based on varying particle size and varying feeding time. The model predicted inhibition of intestinal uptake or efflux transporters depending on the datasets. The three datasets used formulations with different excipients, which may impact the transporter activity. Model simulations indicated that the model provides a facile framework to predict the impact of transporter inhibition on drug C-t profiles. Model simulations can also be conducted to evaluate the impact of an altered intestinal lumen environment. In conclusion, the rat continuous intestine absorption model may provide a useful tool to predict the impact of varying drug formulations on rat oral absorption profiles.

Multi-layer Raman chemical mapping to investigate the effect of API particle size and blending shear rate on API domain sizes in pharmaceutical tablets

While macromixing (gross uniformity) has received a lot of attention in pharmaceutical powder blending, micromixing (particularly, particle-level aggregation) has been significantly less studied. This study investigated the impact of active pharmaceutical ingredient (API) particle size (D50: 11, 28, and 70 µm) and blending shear rate (low and high) that was caused by tumbling blending (specifically, a V-blender) on micro-mixing. The effect on micro-mixing (API domain sizes) was assessed in direct compression tablets using high-resolution Raman chemical mapping. Analyses of multiple layers within tablets enabled a more reliable understanding of the variability in API domain sizes with respect to the independent variables. The relationship between API domain sizes and the manufactured tablets' content uniformity (CU) was also investigated using near-infrared transmission spectroscopy. Generally, at low shear, as the API particle size decreased, the frequency and size of API agglomerates increased, resulting in poor CU. However, in all cases, API domain sizes drastically reduced at high shear, resulting in an acceptable CU. The results of this work clearly demonstrated the utility of a multi-layer, multi-tablet, and high-resolution Raman chemical mapping as an off-line process analytical technology (PAT) system, to enable quality-by-design driven formulation and process development.

Measuring Bismuth Oxide Particle Size and Morphology in Film-Coated Tablets.

The assessment of active pharmaceutical ingredient (API) particle size and morphology is of great importance for the pharmaceutical industry since it is expected to significantly affect physicochemical properties. However, very few methods are published for the determination of API morphology and particle size of film-coated (FC) tablets. In the current study we provide a methodology for the measurement of API particle size and morphology which could be applied in several final products. Bismuth Oxide 120 mg FC Tabs were used for our method development, which contain bismuth oxide (as tripotassium dicitratobismuthate (bismuth subcitrate)) as the active substance. The sample preparation consists of partial excipient dissolution in different solvents. Following this procedure, the API particles were successfully extracted from the granules. Particle size and morphology identification in Bismuth Oxide 120 mg FC Tabs was conducted using micro-Raman mapping spectroscopy and ImageJ software. The proposed methodology was repeated for the raw API material and against a reference listed drug (RLD) for comparative purposes. The API particle size was found to have decreased compared to the raw API, while the API morphology was also affected from the formulation manufacturing process. Comparison with the RLD product also revealed differences, mainly in the API particle size and secondarily in the crystal morphology.

In-Depth Understanding of Granule Compression Behavior under Variable Raw Material and Processing Conditions.

Tablet manufacturing involves the processing of raw materials through several unit operations. Thus, the mitigation of input-induced variability should also consider the downstream processability of intermediary products. The objective of the present work was to study the effect of variable raw materials and processing conditions on the compression properties of granules containing two active pharmaceutical ingredients (APIs) and microcrystalline cellulose. Differences in compressibility and tabletability of granules were highlighted in function of the initial particle size of the first API, granule polydispersity and fragmentation. Moreover, interactions were underlined with the atomizing pressure. Changing the supplier of the second API was efficiently controlled by adapting the binder addition rate and atomizing pressure during granulation, considering the starting crystal size. By fitting mathematical models on the available compression data, the influence of diluent source on granule compactibility and tabletability was identified. These differences resumed to the ease of compaction, tableting capacity and pressure sensitivity index due to variable water binding capacity of microcrystalline cellulose. Building the design space enabled the identification of suitable API types and the appropriate processing conditions (spray rate, atomizing pressure, compression force) required to ensure the desired tableting performance.

QbD-Based Development and Validation of Novel Stability-Indicating Method for the Assay and Dissolution of Garenoxacin in Garenoxacin Tablets.

Garenoxacin mesylate is a novel des-fluoro(6) quinolone, approved and marketed for human use in Japan under the name Geninax. In this current work, a simple and stability-indicating method for the assay and dissolution of garenoxacin in garenoxacin tablets 200 mg was performed. New method developed for the particle size measurement of Garenoxacin mesylate Active Pharmaceutical Ingredient using Malvern 2000. A quality by design (QbD)-based stability-indicating assay method was developed using 0.1% (v/v) formic acid in water and methanol (70:30). Using a photodiode array detector the peak purity of the garenoxacin peak for all degradation samples was studied. The biopharmaceutical classification system (BCS) solubility of garenoxacin mesylate active pharmaceutical ingredient (API) was studied by a modified shake flask method. A dissolution test method was developed using 0.1 N hydrochloric acid as the medium, United State Pharmacopoeia apparatus-II (paddle), revolution per minute (rpm) 50, temperature 37 ± 0.5°C and time 30 min. Liquid paraffin was used as the dispersant in the particle size measurement of garenoxacin mesylate API using the Malvern Mastersizer-wet method. The QbD-based RP-HPLC method was stability-indicating, simple, precise, and accurate. The assay method was linear over 12.5 to 75 µg/mL at the detection wavelength of 280 nm. A UV-based method was developed and validated for the dissolution of garenoxacin 200 mg tablets and the method was found to be linear over 2.9 to 34.2 µg/mL at 280 nm. Based on data, the dissolution tolerance for garenoxacin 200 mg tablets was proposed as Q not less than 80% at time 30 min (% drug released with respect to label claim (Q). The effect of garenoxacin mesylate API particle size in the tablet dosage form was studied using particles of 92 µm and 220 µm [90% of the total particles are smaller than this size (D90)] and it was found that there was no impact on the in vitro dissolution profile. The reported stability-indicating assay and dissolution test methods can be used in regular QC testing of garenoxacin 200 mg tablets. The Malvern particle size wet dispersion measurement method developed and validated for garenoxacin mesylate API is simple and robust. A QbD based RP-HPLC method (using Design Expert Software version 11) was developed and studied peak purity of Garenoxacin peak using Photo Diode Array detector (for all degradation samples, control sample and standard solution) and the same method is validated following USP and ICH guidelines.LC-MS compatible volatile buffer solution is used in the preparation of the mobile phase for the novel stability-indicating RP-HPLC assay method.

Application of reverse engineering in the field of pharmaceutical tablets using Raman mapping and chemometrics

Raman micro-spectroscopy technique offers a combination of relatively high spatial resolution with identification of components or mixtures of components in different sample areas, e.g. on the surface or the cross-section of a sample. This study is focused on the analysis of the tablets from pharmaceutical development with different technological parameters: (1) the manufacturing technology, (2) the particle size of the input API (active pharmaceutical ingredient) and (3) the quantitative composition of the individual excipients.These three mentioned parameters represent the most frequently solved problems in the field of reverse engineering in pharmacy. The investigation aims to distinguish tablets with the above-described technological parameters with limited subjective steps by Raman microscopy. Furthermore, non-subjective methods of Raman data analysis using advanced statistical analysis have been proposed, namely Principal Component Analysis, Soft Independent Modelling of Class Analogy and Linear Discriminant Analysis. The methods successfully distinguished and identified even very small differences in the analysed tablets within our study and provided objective statistic evaluation of Raman maps. The information on component and particle size distribution including their small differences, which is the critical parameter in the development of the original and generic products, was obtained due to combination of these methods. Even though each of these chemometric methods evaluates the data set from a different perspective, their mutual application on the problem of Raman maps evaluation confirmed and specified results on level that would be unattainable with the use of only one them.

Analyzing ophthalmic suspension particle size distributions using laser diffraction: Placebo background subtraction method

The current study demonstrated that the presence of excipients can interfere with the measurement of particle size distribution (PSD), a critical quality attribute of ophthalmic suspensions, by laser diffraction (LD) and that a placebo background subtraction approach can eliminate the impact of excipients on the PSD measurement. Commercially available loteprednol etabonate and brinzolamide ophthalmic suspensions were used as model suspensions. The impact of excipients in these formulations on the LD measurements was determined using a one-factor-at-a-time experimental design approach, using National Institute of Standards and Technology (NIST) traceable polystyrene particle size standards as references. Among the evaluated excipients, polymers containing polyacrylic acid were found to interfere with the PSD analysis by creating the LD signals correspond to particles ranging from a few micrometers to a hundred micrometers in size. As a result, the measured PSD of active pharmaceutical ingredient (API) particles in the formulation overlapped with or superimposed on the excipient PSD signal, leading to erroneous interpretation of the API particle size. Additionally, dispersion of brinzolamide particles in unsaturated solutions led to rapid dissolution of brinzolamide particles during the measurement, resulting in underestimation of the particle size range. Here, a placebo background subtraction approach was developed to eliminate the interference of the excipients. This newly developed LD method was also evaluated using orthogonal methods, including polarized light microscopy and scanning electron microscopy (SEM). The strategy used in this study to eliminate the interference of excipients may also be useful for other heterogeneous dispersions where excipient interference may be of concern.

Predicting the effect of prandial stage and particle size on absorption of ODM-204

The prediction of absorption properties plays a key role in formulation development when the compound under development shows poor solubility and its absorption is therefore presumed to be solubility limited. In our work, we combined and compared data obtained from in vitro dissolution tests, transit intestinal model studies (TIM-1) and physiologically based pharmacokinetic modelling. Our aim was to determine the ability of these methods to predict performance of poorly soluble lipophilic weak base in vivo. The validity of the predictive methods was evaluated against the in vivo clinical pharmacokinetic (PK) data obtained after administration of the first test formulation, T1. The aim of our study was to utilize the models in evaluating absorption properties of the second test formulation, T2, which has not yet been clinically administered.The compound in the studies was ODM-204, which is a novel, orally administered, investigational, nonsteroidal dual inhibitor of CYP17A1 and androgen receptor. Owing to its physicochemical properties ODM-204 is prone to low or variable bioavailability.The models examined provided congruent data on dose dependent absorption, food effect at a dose of 200 mg and on the effect of API (active pharmaceutical ingredient) particle size on absorption. Our study shows that the predictive tools of in vitro dissolution, TIM-1 system and the PBPK (physiologically based pharmacokinetic) simulation, showed predictive power of different mechanisms of bioavailability and together provided valuable information for decision making.

Underpinning mechanistic understanding of the segregation phenomena of pharmaceutical blends using a near-infrared (NIR) spectrometer embedded segregation tester

The segregation of an active pharmaceutical ingredient (API) within a powder blend is one of the major manufacturing obstacles in achieving content uniformity. Segregation can be due to differences in physicochemical properties of formulation components and/or perturbations experienced during secondary processing steps, such as granulation, fluidization, die-filling and compression. A near-infrared (NIR) spectrometer embedded segregation tester, which could mimic the external stimulations (vibration and fluidization) experienced by a blend in a manufacturing facility, was used to evaluate and predict blend segregation. Two different GlaxoSmithKline (GSK) product blends with variations in the API particle size and concentration were tested. Drug content was further measured at different locations along the powder bed by NIR to sketch the segregation profile and calculate the overall segregation intensity of each blend. The study indicated that the segregation potential was dependent on the particle sizes of API and excipients, as well as the type of stimulus applied (vibration vs fluidization). Drug concentration profiles obtained from this mode of analysis decoded the underlying segregation mechanisms (sieving, trajectory and air elutriation) easily. The employed NIR-based segregation tester proved to be a useful small-scale predictive tool to evaluate and rank the segregation risk of the studied pharmaceutical blends.

Comparison between twin-screw and high-shear granulation - The effect of filler and active pharmaceutical ingredient on the granule and tablet properties

The aim of the study was to compare continuous twin-screw granulation (TSG) with batch-wise high-shear granulation (HSG). Two different formulations containing either microcrystalline cellulose (MCC) and mannitol or MCC and dibasic calcium phosphate (DCP) as fillers were used. Three different active pharmaceutical ingredients (APIs) (allopurinol, paracetamol and metformin HCl) were used as model substances. To find the suitable liquid-to-solid (L/S) ratio for the granulations, preliminary trials were carried out using a mixer torque rheometry (MTR). Both granule and tablet properties were studied. Granules were characterized with respect to particle size distribution and flowability, while tablets were analysed for tensile strength. Both granulation techniques produced granules with unimodal particle size distribution after milling with the selected L/S ratios. Continuous TSG was less sensitive for liquid amount than HSG when comparing the granule size and tensile strength of tablets. The tabletability of the MCC-DCP formulation was decreased after the wet granulation, whereas the tabletability of MCC-mannitol was increased after wet granulation. Tablets made of TSG granules had a higher tensile strength than HSG tablets for all formulations. Even the APIs with poor compaction properties produced tablets with sufficient tensile strength. All the model substances behaved in a same way independently of the particle size and solubility of the pure API. These findings confirmed that continuous twin-screw granulation is a good alternative to batch-wise high-shear granulation.

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 - 18-180µm) and loading (0.67-16.67% w/w) on the critical quality attributes of micro-tablets (1.2 and 1.5mm) 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 1.2mm micro-tablets and 2.0mm micro-tablets with 0.67% w/w API loading and coarse API particle size (D90 - 180µm) resulted in CU variability that meets the USP <905> CU acceptance criteria for individual micro-tablets. Apart from the above mentioned 1.2mm 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.

Advantages of Utilizing Population Balance Modeling of Crystallization Processes for Particle Size Distribution Prediction of an Active Pharmaceutical Ingredient

Active pharmaceutical ingredient (API) particle size distribution is important for both downstream processing operations and in vivo performance. Crystallization process parameters and reactor configuration are important in controlling API particle size distribution (PSD). Given the large number of parameters and the scale-dependence of many parameters, it can be difficult to design a scalable crystallization process that delivers a target PSD. Population balance modeling is a useful tool for understanding crystallization kinetics, which are primarily scale-independent, predicting PSD, and studying the impact of process parameters on PSD. Although population balance modeling (PBM) does have certain limitations, such as scale dependency of secondary nucleation, and is currently limited in commercial software packages to one particle dimension, which has difficulty in predicting PSD for high aspect ratio morphologies, there is still much to be gained from applying PBM in API crystallization processes.

Managing API raw material variability during continuous twin-screw wet granulation

Very few studies have investigated the impact of raw material variability upon the granule critical quality attributes (CQAs) produced via twin-screw wet granulation (i.e., granule size distribution, density, flowability). In this study, the impact of the raw material variability of an active pharmaceutical ingredient (API) in a high dose formulation on the twin-screw wet granulation process and on the resulting granule quality attributes was investigated. In a previous study (Stauffer et al., 2018), eight API batches were characterized to determine the API batch-to-batch variability. Principal component analysis (PCA) was then used to analyse the raw material property differences between the API batches and to determine the causes of the batch-to-batch variability. In current study, the three principal components from that PCA model were used as factors together with twin-screw granulation process parameters (i.e., screw speed and liquid-to-solid ratio) in a D-optimal screening design of experiments to understand the influence of these factors upon the granule CQAs. It was found that the API particle size distribution and related properties (e.g., density, agglomeration profile) were critical for the granule CQAs. In a next step, the significant factors from the screening design results were used to determine the design space of the twin-screw granulation process for the studied formulation via a D-optimal optimisation design, herewith controlling the risk of failure for the potential API raw material variability. The possibility to obtain suitable granule CQAs with a risk of failure of 1% for all API batches was demonstrated. It was thus possible to identify a combination of process parameters that can manage the API batch-to-batch variability leading to granules with pre-defined suitable CQAs.