Low Active Pharmaceutical Ingredients Research Articles

Morusin-Cu(II)-indocyanine green nanoassembly ignites mitochondrial dysfunction for chemo-photothermal tumor therapy

Nanoscale drug delivery systems derived from natural bioactive materials accelerate the innovation and evolution of cancer treatment modalities. Morusin (Mor) is a prenylated flavonoid compound with high cancer chemoprevention activity, however, the poor water solubility, low active pharmaceutical ingredient (API) loading content, and instability compromise its bioavailability and therapeutic effectiveness. Herein, a full-API carrier-free nanoparticle is developed based on the self-assembly of indocyanine green (ICG), copper ions (Cu2+) and Mor, termed as IMCNs, via coordination-driven and π-π stacking for synergistic tumor therapy. The IMCNs exhibits a desirable loading content of Mor (58.7 %) and pH/glutathione (GSH)-responsive motif. Moreover, the photothermal stability and photo-heat conversion efficiency (42.8 %) of IMCNs are improved after coordination with Cu2+ and help to achieve photothermal therapy. Afterward, the released Cu2+ depletes intracellular overexpressed GSH and mediates Fenton-like reactions, and further synergizes with ICG at high temperatures to expand oxidative damage. Furthermore, the released Mor elicits cytoplasmic vacuolation, expedites mitochondrial dysfunction, and exerts chemo-photothermal therapy after being combined with ICG to suppress the migration of residual live tumor cells. In vivo experiments demonstrate that IMCNs under laser irradiation could excellently inhibit tumor growth (89.6 %) through the multi-modal therapeutic performance of self-enhanced chemotherapy/coordinated-drugs/ photothermal therapy (PTT), presenting a great potential for cancer therapy.

Microwave-Assisted Freeze-Drying: Impact of Microwave Radiation on the Quality of High-Concentration Antibody Formulations.

Microwave-assisted freeze-drying (MFD) offers significant time savings compared to conventional freeze-drying (CFD). While a few studies have investigated the stability of biopharmaceuticals with low protein concentrations after MFD and storage, the impact of MFD on high-concentration monoclonal antibody (mAb) formulations remains unclear. In this study, we systematically examined the effect of protein concentration in MFD and assessed protein stability following MFD, CFD, and subsequent storage using seven protein formulations with various stabilizers and concentrations. We demonstrated that microwaves directly interact with the active pharmaceutical ingredient (API), leading to decreased physical stability, specifically aggregation, in high-concentration antibody formulations. Furthermore, typically used sugar:protein ratios from CFD were insufficient for stabilizing mAbs when applying microwaves. We identified the intermediate drying phase as the most critical for particle formation, and cooling the samples provided some protection for the mAb. Our findings suggest that MFD technology may not be universally applicable to formulations well tested in CFD and could be particularly beneficial for formulations with low API concentrations requiring substantial amounts of glass-forming excipients, such as vaccines and RNA-based products.

Continuous Spatiotemporal Therapy of A Full-API Nanodrug via Multi-Step Tandem Endogenous Biosynthesis

Nanomedicine holds great promise to enhance cancer therapy. However, low active pharmaceutical ingredient (API) loading content, unpredictable drug release, and potential toxicity from excipients limit their translational capability. We herein report a full-API nanodrug composed of FDA-approved 5-aminolevulinic acid (ALA), human essential element Fe3+, and natural bioactive compound curcumin with an ideal API content and pH-responsive release profile for continuous spatiotemporal cancer therapy achieved by multi-step tandem endogenous biosynthesis. First, ALA enzymatically converts into photosensitizer protoporphyrin IX (PpIX). Afterward, multiple downstream products including carbon monoxide (CO), Fe2+, biliverdin (BV), and bilirubin (BR) are individually biosynthesized through the PpIX-heme-CO/Fe2+/BV-BR metabolic pathway, further cooperating with released Fe3+ and curcumin, ultimately eliciting mitochondria damage, membrane disruption, and intracytoplasmic injury. This work not only provides a paradigm for exploiting diversified metabolites for tumor suppression, but also presents a safe and efficient full-API nanodrug, facilitating the practical translation of nanodrugs.

Evaluating Spray Drying and Co-Precipitation as Manufacturing Processes for Amorphous Solid Dispersions of a Low Tg API

Amorphous solid dispersions feature prominently in the approach to mitigate low bioavailability of poorly water-soluble small molecules, particularly in the early development space focusing on toxicity evaluations and clinical studies in normal healthy volunteers, where high exposures are needed to establish safety margins. Spray drying has been the go-to processing route for a number of reasons, including ubiquitous availability of equipment, the ability to accommodate small scale deliveries, and established processes for delivering single phase amorphous material. Active pharmaceutical ingredients (APIs) with low glass transition temperatures (Tg) can pose challenges to this approach. This study addresses multiple routes towards overcoming issues encountered with a low Tg (∼ 12 °C) API during manufacture of a spray dry intermediate (SDI). Even once formulated as an amorphous solid dispersion (ASD) with HPMCAS-LG, the Tg of the ASD was sufficiently low to require the use of non-ideal solvents, posing safety concerns and ultimately resulting in low yields with frequent process interruptions to resolve product build-up. To resolve challenges with spray drying the HPMCAS-L SDI, higher Tg polymers were assessed during spray drying, and an alternative antisolvent precipitation-based process was evaluated to generate co-precipitated amorphous dispersions (cPAD) with either HPMCAS-L or the additional higher Tg polymers. Both approaches were found to be viable alternatives to achieve single phase ASDs while demonstrating comparable in vitro and in vivo bioperformance compared to the SDI. The results of this effort offer valuable considerations for future early-stage activities for ASDs with low Tg APIs.

Usefulness of the BioGIT system in screening for differences in early exposure in the fasted state on an a priori basis

The objective of the present study was to confirm the usefulness of BioGIT data in the evaluation of the impact of dose and/or formulation on early exposure after oral administration of immediate release or enabling products of low solubility active pharmaceutical ingredients (APIs) with a glass of water in the fasted state. BioGIT experiments were performed with four APIs: Compound Α (tablet, three dose levels), Compound E (capsule PiC1, capsule PiC2 and tablet), fenofibrate (Lipidil® capsule and Lipidil 145 ONE® tablet) and Compound F (HP-β-CD aqueous solution and tablet). Based on mean plasma AUC0-60min values which became available after completion of the BioGIT experiments, mean BioGIT AUC0-50min values were useful for the evaluation of the impact of dose and/or formulation on early exposure. The log-transformed ratios of mean BioGIT AUC0-50min values for two doses and/or two formulations estimated in this study and in a recent study for two diclofenac potassium products (Cataflam® tablet and Voltfast® sachet, same dose) vs. the corresponding log-transformed ratios of mean plasma AUC0-60min values (n = 7 pairs of ratios), were included in a previously established correlation between log-transformed ratios of mean BioGIT AUC0–50min values and log-transformed ratios of plasma AUC0–60min values (n = 9 pairs of ratios). The correlation between log-transformed plasma AUC0–60min ratios vs. log-transformed BioGIT AUC0–50min ratios was confirmed (n = 16 pairs of ratios, R = 0.90). Compared with the previously established correlation the statistical characteristics were improved. Based on this study, the BioGIT system could be useful as a screening tool for assessing the impact of dose and/or formulation differences on early exposure, after administration of immediate release or enabling drug products of low solubility APIs with a glass of water in the fasted state, on an a priori basis.

Assessment of Resonant Acoustic Mixing for Low-Dose Pharmaceutical Powder Blends.

Obtaining a homogeneous low-dose pharmaceutical powder blend without multi-step processing remains a challenge. One promising technology to address this risk is resonant acoustic mixing (RAM). In this study, the performance of a laboratory resonant acoustic mixer (LabRAM) was studied at low active pharmaceutical ingredient (API) concentrations (0.1-0.5% w/w), using three commercial grades of a model API (Acetaminophen) and diluents with varying physical properties. The performance was assessed by evaluating blend uniformity (BU) and capsule content uniformity (CU) as a function of mixing time. Overall, the LabRAM achieved acceptable BU in a single step even at 0.1% w/w drug loading. A reduction in API primary particle size led to improved mixing efficiency and uniformity. Moreover, the presence of surface cavities in the diluents used appeared to have led to improved uniformity. The results demonstrated that RAM could achieve uniform powder blends without multi-step processing, for low-dose formulations.

Solubilizing temperature of crystalline drug in polymer carrier: A rheological investigation on a posaconazole-copovidone system with low drug load

Measuring the solubility of a crystalline active pharmaceutical ingredient (API) in a polymer-rich system is challenging due to the high viscosity of the polymer which kinetically impedes reaching the solubility equilibrium. In this study, a rheological approach of determining the solubilizing temperature of a crystalline API in a polymeric carrier has been developed. To validate the method, a model physical mixture of crystalline posaconazole and copovidone with a relatively low API load (25 wt%) was utilized. First, a comparison between conventional differential scanning calorimetry (DSC) and a rheological temperature ramp was conducted to illustrate that the rheological method could capture the melting point depression behavior similarly to the more well-known DSC technique. Second, to further understand the dissolution process of the crystalline posaconazole into the copovidone carrier and precisely measure the solubilizing temperature, a series of isothermal rheological time sweeps were carried out at various temperatures selected based on the rheological temperature sweep. Because the dissolved API molecule imparted a plasticizing effect to the polymeric carrier, the complex viscosity of the API-polymer system decreased gradually over time and correlated well to an exponential decay function. Moreover, dependent on the applied temperature, the API-polymer system eventually accomplished distinct equilibrium states (complex viscosities) within different time frames. The obtained time constants at different temperatures were fitted to the Arrhenius equation, allowing the determination of the activation energy of the mixing process. The results indicated that once the processing temperature exceeded a critical point below the melting point of the crystalline API, the API-polymer solubilization process switched from a surface dominated dispersive mechanism to a molecular-level solubilization mode, manifested by the significantly increased activation energy. To the best of our knowledge, the currently developed rheological approach was the first successful measurement of the solubilizing temperature of a crystalline drug in a polymer-rich system.

Development and characterization of ibuprofen co-crystals granules prepared via fluidized bed granulation in a one-step process – a design of experiment approach

Objective The focus of this study was to investigate the possibility of producing ibuprofen-nicotinamide (IBU-NIC) and ibuprofen-isonicotinamide (IBU-INA) cocrystal-containing granules, using a one-step fluidized bed dryer granulation manufacturing process, and evaluate their mechanical properties. Significance Pharmaceutical cocrystals represent a suitable strategy to improve properties of active pharmaceutical ingredients (APIs), such as solubility and processability. Ibuprofen (IBU) is a small molecule API which can form cocrystals with different coformers, including NIC and INA. An improvement in mechanical properties for IBU-NIC cocrystals relative to IBU was previously reported but, to date, the formulation of IBU cocrystals in a solid dosage form has not been investigated. Methods In situ cocrystallization and granulation were achieved concurrently by processing in a lab-scale fluidized bed granulator following a design of experiment (DoE) approach using a two-level factorial design with both process and formulation variables. Solid-state, micrometric, dissolution, and mechanical (tabletability) characteristics of granules were assessed post-processing. Results Granules containing cocrystals were successfully prepared for 11 of 16 DoE runs. Parameters with a significant effect on granule drug loading, flow function, porosity, and size could be identified from the DoE model. Process yield was increased by using a high inlet temperature at high solution feed rate. To avoid the formation of sticky particles, caking and over-wetting of the powder during the process, the utilization of high inlet temperature, low API + coformer:filler ratio, low API concentration in solution and low solution feed rate were suggested by the model. Conclusion The multivariable model developed enables accurate optimization of the granulation process for IBU cocrystals.

Novel Cleaning-in-Place Strategies for Pharmaceutical Hot Melt Extrusion.

To avoid any type of cross-contamination, residue-free production equipment is of utmost importance in the pharmaceutical industry. The equipment cleaning for continuous processes such as hot melt extrusion (HME), which has recently gained popularity in pharmaceutical applications, necessitates extensive manual labour and costs. The present work tackles the HME cleaning issue by investigating two cleaning strategies following the extrusion of polymeric formulations of a hormonal drug and for a sustained release formulation of a poorly soluble drug. First, an in-line quantification by means of UV–Vis spectroscopy was successfully implemented to assess very low active pharmaceutical ingredient (API) concentrations in the extrudates during a cleaning procedure for the first time. Secondly, a novel in-situ solvent-based cleaning approach was developed and its usability was evaluated and compared to a polymer-based cleaning sequence. Comparing the in-line data to typical swab and rinse tests of the process equipment indicated that inaccessible parts of the equipment were still contaminated after the polymer-based cleaning procedure, although no API was detected in the extrudate. Nevertheless, the novel solvent-based cleaning approach proved to be suitable for removing API residue from the majority of problematic equipment parts and can potentially enable a full API cleaning-in-place of a pharmaceutical extruder for the first time.

A random survey of the prevalence of falsified and substandard antibiotics in the Lao PDR.

In 2012, a stratified random survey, using mystery shoppers, was conducted to investigate the availability and quality of antibiotics sold to patients in the private sector in five southern provinces of the Lao People's Democratic Republic (Laos). A total of 147 outlets were sampled in 10 districts. The active pharmaceutical ingredient (API) content measurements for 909 samples, including nine APIs (amoxicillin, ampicillin, ceftriaxone, ciprofloxacin, doxycycline, ofloxacin, sulfamethoxazole, tetracycline and trimethoprim), were determined using HPLC. All the analysed samples contained the stated API and we found no evidence for falsification. All except one sample had all the units tested with %API values between 75% and 125% of the content stated on the label. However, we identified the presence of substandard antibiotics: 19.6% (201/1025) of samples had their units outside the 90%-110% content of the label claim and 60.2% (617/1025) of the samples had units outside of the International Pharmacopoeia uniformity of content limit range. Amoxicillin had a high number of samples [67.1% (151)] with units above the limit range, followed by ciprofloxacin [58.8% (10)] and ofloxacin [57.4% (39)]. Ceftriaxone, trimethoprim and sulfamethoxazole had the highest number of samples with low API content: 57.1% (4), 51.6% (64) and 34.7% (43), respectively. Significant differences in %API were found between stated countries of manufacture and stated manufacturers. With the global threat of antimicrobial resistance to patient outcomes, greater understanding of the role of poor-quality antibiotics is needed. Substandard antibiotics will have reduced therapeutic efficacy, impacting public health and control of bacterial infections.

Comparison between integrated continuous direct compression line and batch processing – The effect of raw material properties

There is a current trend in pharmaceutical manufacturing to shift from traditional batch manufacture to continuous manufacturing. The purpose of this study was to test the ability of an integrated continuous direct compression (CDC) line, in relation to batch processing, to achieve consistent tablet quality over long processing periods for formulations with poor flow properties or with a tendency to segregate. The study design included four industrially relevant formulations with different segregation indices and flow properties induced through different grades of the Active Pharmaceutical Ingredient (API), paracetamol, and major filler as well as varying the amount of API. The performance metrics investigated were content, uniformity of content, tablet weight, and tablet strength. The overall process stability over time was significantly improved with the CDC line as compared to the batch process. For all the formulations with a high API content, the CDC line provided better or equal uniformity of content and tablet weight as compared to batch. The CDC line was especially efficient in providing a stable content and tablet weight for poorly flowing formulations containing the standard, cohesive, grade of API. The only formulation that performed better in the batch process was the formulation with a low API content. Thus, for this formulation, the batch process achieved lower variation in tablet content since maintaining a low feed rate for the API proved challenging in the CDC line. In addition, some of the API became stuck in the CDC line between feeding and tableting, most likely at the funnel in the mixer inlet, highlighting the need for properly designed interfaces between units. The insensitivity of the CDC line towards poor flow indicates that one could use direct compression at high drug load compositions of poorly flowing powder blends that could not be processed via batch manufacturing.

Mimicking DNA alkylation: Removing genotoxin impurities from API streams with a solvent stable polybenzimidazole-adenine polymer

This study reports the application of a novel polybenzimidazole (PBI) polymer modified with an alkylated DNA base - adenine - as an effective scavenger for several families of DNA alkylating agents. This new material addresses an important issue in active pharmaceutical ingredients (APIs) manufacture, the removal of genotoxic impurities (GTIs) to strictly low regulated limits. Instead of targeting individual GTIs removal, PBI-adenine scavenger mimics the concept of DNA-GTI adduct formation that takes place in vivo, but in this case, in an organic solvent matrix where APIs are chemically synthesized. Removal of eleven GTIs from five different chemical families is assessed with >80% removal. Slow binding kinetics for some GTIs at room temperature was identified as one of the limitations of the PBI-adenine polymer. API purification is addressed and an efficient process is presented for two APIs studied, mometasone furoate and betamethasone acetate, affording high impurity removals (>96%) and high API recovery with low API loss (3.5%) for these case studies. The possible application of this straightforward strategy in API post-reaction stream purification, is able to attain GTI imposed limits as low as 0.6 mg GTI/g API respecting the Threshold of Toxicological Concern (TTC) value.

DNP-enhanced solid-state NMR spectroscopy of active pharmaceutical ingredients.

Solid-state NMR spectroscopyhas become a valuable tool for the characterization of both pure and formulated active pharmaceutical ingredients (APIs). However, NMR generally suffers from poor sensitivity that often restricts NMR experiments to nuclei with favorable properties, concentrated samples, and acquisition of one-dimensional (1D) NMR spectra. Here, we review how dynamic nuclear polarization (DNP) can be applied to routinely enhance the sensitivity of solid-state NMR experiments by one to two orders of magnitude for both pure and formulated APIs. Sample preparation protocols for relayed DNP experiments and experiments on directly doped APIs are detailed. Numerical spin diffusion models illustrate the dependence of relayed DNP enhancements on the relaxation properties and particle size of the solids and can be used for particle size determination when the other factors are known. We then describe the advanced solid-state NMR experiments that have been enabled by DNP and how they provide unique insight into the molecular and macroscopic structure of APIs. For example, with large sensitivity gains provided by DNP, natural isotopic abundance, 13 C-13 C double-quantumsingle-quantum homonuclear correlation NMR spectra of pure APIs can be routinely acquired. DNP also enables solid-state NMR experiments with unreceptive quadrupolar nuclei such as 2 H, 14 N, and 35 Cl that are commonly found in APIs. Applications of DNP-enhanced solid-state NMR spectroscopyfor the molecular level characterization of low API load formulations such as commercial tablets and amorphous solid dispersions are described. Future perspectives for DNP-enhanced solid-state NMR experiments on APIs are briefly discussed.

On Identification of Critical Material Attributes for Compression Behaviour of Pharmaceutical Diluent Powders.

As one of the commonly-used solid dosage forms, pharmaceutical tablets have been widely used to deliver active drugs into the human body, satisfying patient’s therapeutic requirements. To manufacture tablets of good quality, diluent powders are generally used in formulation development to increase the bulk of formulations and to bind other inactive ingredients with the active pharmaceutical ingredients (APIs). For formulations of a low API dose, the drug products generally consist of a large fraction of diluent powders. Hence, the attributes of diluents become extremely important and can significantly influence the final product property. Therefore, it is essential to accurately characterise the mechanical properties of the diluents and to thoroughly understand how their mechanical properties affect the manufacturing performance and properties of the final products, which will build a sound scientific basis for formulation design and product development. In this study, a comprehensive evaluation of the mechanical properties of the widely-used pharmaceutical diluent powders, including microcrystalline cellulose (MCC) powders with different grades (i.e., Avicel PH 101, Avicel PH 102, and DG), mannitol SD 100, lactose monohydrate, and dibasic calcium phosphate, were performed. The powder compressibility was assessed with Heckel and Kawakita analyses. The material elastic recovery during decompression and in storage was investigated through monitoring the change in the dimensions of the compressed tablets over time. The powder hygroscopicity was also evaluated to examine the water absorption ability of powders from the surroundings. It was shown that the MCC tablets exhibited continuous volume expansion after ejection, which is believed to be induced by (1) water absorption from the surrounding, and (2) elastic recovery. However, mannitol tablets showed volume expansion immediately after ejection, followed by the material shrinkage in storage. It is anticipated that the expansion was induced by elastic recovery to a limited extent, while the shrinkage was primarily due to the solidification during storage. It was also found that, for all powders considered, the powder compressibility and the elastic recovery depended significantly on the particle breakage tendency: a decrease in the particle breakage tendency led to a slight decrease in the powder compressibility and a significant drop in immediate elastic recovery. This implies that the particle breakage tendency is a critical material attribute in controlling the compression behaviour of pharmaceutical powders.

Analysis of low active-pharmaceutical-ingredient signal drugs based on thin layer chromatography and surface-enhanced Raman spectroscopy

Active pharmaceutical ingredients (API) embedded in the excipients of the formula can usually be unravelled by normal Raman spectroscopy (NRS). However, more and more drugs with low API content and/or low Raman scattering coefficient were insensitive to NRS analysis, which was for the first time defined as Low API-Signal Drugs (LASIDs) in this paper. The NRS spectra of these LASIDs were similar to their dominant excipients’ profiles, such as lactose, starch, microcrystalline cellulose (MCC), etc., and were classified into three types as such. 21 out of 100 kinds of drugs were screened as LASIDs and characterized further by Raman microscopic mapping. Accordingly, we proposed a tailored solution to the qualitation and quantitation problem of these LASIDs, using surface-enhanced Raman spectroscopic (SERS) detection on the thin layer chromatographic (TLC) plate both in situ and after-separation. Experimental conditions and parameters including TLC support matrix, SERS substrate, detection mode, similarity threshold, internal standard, etc., were optimized. All LASIDs were satisfactorily identified and the quantitation results agreed well with those of high performance liquid chromatography (HPLC). For some structural analogues of LASIDs, although they presented highly similar SERS spectra and were tough to distinguish even with Raman microscopic mapping, they could be successfully discriminated from each other by coupling SERS (with portable Raman spectrometer) with TLC. These results demonstrated that the proposed solution could be employed to detect the LASIDs with high accuracy and cost-effectiveness.

Molecular-Level Control of Ciclopirox Olamine Release from Poly(ethylene oxide)-Based Mucoadhesive Buccal Films: Exploration of Structure-Property Relationships with Solid-State NMR.

Mucoadhesive buccal films (MBFs) provide an innovative way to facilitate the efficient site-specific delivery of active compounds while simultaneously separating the lesions from the environment of the oral cavity. The structural diversity of these complex multicomponent and mostly multiphase systems as well as an experimental strategy for their structural characterization at molecular scale with atomic resolution were demonstrated using MBFs of ciclopirox olamine (CPX) in a poly(ethylene oxide) (PEO) matrix as a case study. A detailed description of each component of the CPX/PEO films was followed by an analysis of the relationships between each component and the physicochemical properties of the MBFs. Two distinct MBFs were identified by solid-state NMR spectroscopy: (i) at low API (active pharmaceutical ingredient) loading, a nanoheterogeneous solid solution of CPX molecularly dispersed in an amorphous PEO matrix was created; and (ii) at high API loading, a pseudoco-crystalline system containing CPX-2-aminoethanol nanocrystals incorporated into the interlamellar space of a crystalline PEO matrix was revealed. These structural differences were found to be closely related to the mechanical and physicochemical properties of the prepared MBFs. At low API loading, the polymer chains of PEO provided sufficient quantities of binding sites to stabilize the CPX that was molecularly dispersed in the highly amorphous semiflexible polymer matrix. Consequently, the resulting MBFs were soft, with low tensile strength, plasticity, and swelling index, supporting rapid drug release. At high CPX content, however, the active compounds and the polymer chains simultaneously cocrystallized, leaving the CPX to form nanocrystals grown directly inside the spherulites of PEO. Interfacial polymer-drug interactions were thus responsible not only for the considerably enhanced plasticity of the system but also for the exclusive crystallization of CPX in the thermodynamically most stable polymorphic form, Form I, which exhibited reduced dissolution kinetics. The bioavailability of CPX olamine formulated as PEO-based MBFs can thus be effectively controlled by inducing the complete dispersion and/or microsegregation and nanocrystallization of CPX olamine in the polymer matrix. Solid-state NMR spectroscopy is an efficient tool for exploring structure-property relationships in these complex pharmaceutical solids.

Rheological and solid-state NMR assessments of copovidone/clotrimazole model solid dispersions

This study aims to assess several model solid dispersions by using dynamic oscillatory rheology, solid-state NMR and other solid phase characterization techniques, and correlate their viscoelastic responses with processing methods and microstructures. A model active pharmaceutical ingredient (API), clotrimazole, was compounded with copovidone to form solid dispersions via various techniques with different mixing capabilities. Physicochemical characterizations of the resulting solid dispersions demonstrated that simple physical mixing led to a poorly mixed blend manifested by existence of large API crystalline content and heterogeneous distribution. Cryogenic milling significantly improved mixing of two components as a result of reduced particle size and increased contact surface area, but produced limited amorphous content. In contrast, hot melt extrusion (HME) processing resulted in a homogenous amorphous solid dispersion because of its inherent mixing efficiency. Storage modulus and viscosities versus frequency of different solid dispersions indicated that the incorporation of API into the polymer matrix resulted in a plasticizing effect which reduced the viscosity. The crystalline/aggregated forms of API also exhibited more elastic response than its amorphous/dispersed counterpart. Temperature ramps of the physical mixture with high API concentration captured a critical temperature, at which a bump was observed in damping factor. This bump was attributed to the dissolution of crystalline API into the polymer. In addition, heating–cooling cycles of various solid dispersions suggested that cryomilling and HME processing could form a homogeneous solid dispersion at low API content, whereas high drug concentration led to a relatively unstable dispersion due to supersaturation of API in the polymer.

Low level drug product API form analysis – Avalide tablet NIR quantitative method development and robustness challenges

Avalide@, a medication used for the treatment of hypertension, is a combination of Irbesartan, and Hydrochlorothiazide. Irbesartan, one of the active pharmaceutical ingredients (API) in Avalide products, exists in two neat crystalline forms: Form A and Form B. Irbesartan Form A is the API form used in a wet granulation for the preparation of Avalide tablets. The presence of the less soluble Irbesartan Form B in Avalide tablets may result in the slower dissolution. In this paper, we have presented our work on the method development, verification and challenges of quantitatively detecting, via NIR and ssNMR, very small amounts of Irbesartan Form B in Avalide tablets. As part of the NIR method development and qualification, limit of detection, linearity and accuracy were examined. In addition, a limited study of the robustness of the method was conducted and a bias in the level of Form B was correlated to the ambient humidity. ssNMR, a primary method for the determination of polymorphic composition, was successfully used as an orthogonal technique to verify the accuracy of the NIR method and added to the confidence in the NIR method. The speed and efficiency of the NIR method make it a suitable and convenient tool for routine analysis of Avalide tablets for Form B in a QC environment.

How do Formulation and Process Parameters Impact Blend and Unit Dose Uniformity? Further Analysis of the Product Quality Research Institute Blend Uniformity Working Group Industry Survey

Responses from the second Product Quality Research Institute (PQRI) Blend Uniformity Working Group (BUWG) survey of industry have been reanalyzed to identify potential links between formulation and processing variables and the measured uniformity of blends and unit dosage forms. As expected, the variability of the blend potency and tablet potency data increased with a decrease in the loading of the active pharmaceutical ingredient (API). There was also an inverse relationship between the nominal strength of the unit dose and the blend uniformity data. The data from the PQRI industry survey do not support the commonly held viewpoint that granulation processes are necessary to create and sustain tablet and capsule formulations with a high degree of API uniformity. There was no correlation between the blend or tablet potency variability and the type of process used to manufacture the product. Although it is commonly believed that direct compression processes should be avoided for low API loading formulations because of blend and tablet content uniformity concerns, the data for direct compression processes reported by the respondents to the PQRI survey suggest that such processes are being used routinely to manufacture solid dosage forms of acceptable quality even when the drug loading is quite low.

Fast assessment of the surface distribution of API and excipients in tablets using NIR-hyperspectral imaging

The inclusion of hyperspectral imaging systems in the manufacturing and development of pharmaceutical products is allowing a successful improvement in the quality control of solid dosage forms. The correct distribution not only of active pharmaceutical ingredient (API) but also of the rest of excipients is essential to assure the correct behavior of the tablet when ingested. This is especially relevant in tablets with low content of potent APIs, in which the prescribed intake dosage frequently corresponds to half-a-tablet. Therefore, the aim of this work is to study the surface distribution of the compounds in tablets with low API content. The proposed procedure includes the scanning of the tablet surface using near infrared hyperspectral spectroscopy in association with multivariate curve resolution (MCR) techniques to obtain selective pictures for each individual compound and to allow the fast assessment of their distribution in the measured surface. As an example, a set of commercial Lorazepam tablets (approximately 1% mass fraction of API, and four excipients) were analyzed. The results obtained show the capacity of the proposed methodology as an expedite approach to evaluate the uniformity of the contents between and within tablets. A method to estimate the homogeneity distribution of API in the two halves of the tablet is also proposed.