Separation Of Active Pharmaceutical Ingredients Research Articles

RP-HPLC Method Development, Validation Including Stability Indicating and Forced Degradation Studies for the Estimation of Pemetrexed in API and Pharmaceutical Dosage Form

Stability indicating analytical RP-HPLC (Reverse Phase- High performance Liquid Chromatography) method was developed for the analysis of the drug in the presence of its degradation products and subsequent validation of Pemetrexed that was conducted in API and pharmaceutical dosage form. Pemetrexed was subjected to different stress conditions as per International Conference on Harmonization (ICH) guidelines, stress conditions applied were including the effect of acid, base, oxidative, hydrolysis, thermal and photolytic degradation conditions. Chromatographic separation of API (Active Pharmaceutical ingredient) was achieved on Water’s HPLC instrument and ODS C18, 250x4.6 mm, 5µm particle size column with gradient elution of 0.1% ortho phosphoric acid buffer: Acetonitrile 80:20 ratio was taken as the eluent (mobile phase). The buffer pH was maintained at 3, the flow rate was 1.0 ml/min and wavelength were detected at 225 nm. The Retention time (RT) of Pemetrexed was Found at 2.9 minutes, column temperature was kept ambient and the runtime was 6 min. System suitability parameters like theoretical plates, tailing factor, and Asymmetry values were showed at 3391, 1.41, and 1.101 respectively. The percentage drug purity was found to be 99.99%. Validation of the method was proved that linear relationship over the range of 25-150 µg/mL, with linear regression curve (correlation coefficient) r2 value was noticed at 0.999 and LOD (limit of detection), LOQ (limit of quantification) values was established at 0.33µg/mL, 0.99µg/mL respectively. Recovery studies carried out at the concentrations of 50%, 100% and 150% with percentage recovery values of 100.06, 99.8 and 99.87 respectively. The precision of intraday was 0.64% and inter-day was 0.95%. Robustness of flow rate and mobile phase was changed even though the method was Robust. Forced degradation studies were also conducted to check the stability and suitability of this method to resolve the degradation products. Method validation was proved to be accurate, precise, linear, repeatable and robust. Thus, the accepted method can be proceeded for the estimation of Pemetrexed in pharmaceutical dosage form in a daily basis, due to their simplicity, suitability, accuracy, robustness and reproducibility.

Quick and Simultaneous Analysis of Dissolved Active Pharmaceutical Ingredients and Formulation Excipients from the Dissolution Test Utilizing UHPLC and Charged Aerosol Detector.

The objective of the study is to develop a quick and simultaneous analysis system for the dissolution of the active pharmaceutical ingredient (API) and the formulation excipient in samples from the dissolution test by UHPLC using the charged aerosol and PDA detectors. The combination of two columns for size-exclusion chromatography (SEC) and the equipment of the charged aerosol detector allowed the quick determination of various water-soluble polymers. Three model sustained-release tablets, each containing a different API of different water solubility (propranolol (soluble), ranitidine (very soluble), and cilostazol (practically insoluble)), were prepared from polyethylene oxide (PEO) matrix to verify the applicability and utility of the analysis system. The dissolution of propranolol was the same as that of PEO, indicating that the diffusion rate of propranolol was consistent with the erosion rate of the PEO and that the dissolution of PRO was based on diffusion. Ranitidine was released faster than PEO, suggesting that ranitidine was diffused through the gel layer of PEO early upon contact with the dissolution medium and before PEO gel erosion. Cilostazol was released slower as compared to PEO, indicating that cilostazol dissolution was based on the polymer's erosion. These results suggested that the analysis system developed in this study is a precise and valid tool to study the dissolution behavior of both APIs and excipients. Optimization of the SEC column for the appropriate separation of APIs and excipients makes the analysis system more efficient and convenient to study the drug release mechanisms and to design formulations.

Construction of ultrathin PTMSP/Porous nanoadditives membranes for highly efficient organic solvent nanofiltration (OSN)

Organic solvent nanofiltration (OSN), also known as solvent resistant nanofiltration (SRNF), has enormous potential for industrial applications. Among the emerging high-performance membrane materials, some have proven challenging to fabricate ultrathin selective layers and at a scale large enough to be practical for industrial consideration. This work demonstrates a facile and scalable solution casting method to prepare ultrathin composite films from advanced polymeric materials and porous additives. Using this method, poly(trimethylsilylpropyne) (PTMSP) membranes could be controlled to just 250 nm thickness resulting in 2 to 30-fold higher solvent permeance than other PTMSP membranes reported to date. Two highly porous additives, poly-dichloroxylene (p-DCX) and Porous Aromatic Framework (PAF-1) were employed to fabricate ultrathin PTMSP composite membranes. Compared to the native PTMSP membrane (methanol permeance of 11.5 L m−2 h−1 bar−1), these additives enhanced membrane permeance by 75% (20.1 L m−2 h−1 bar−1) and 50% (17.2 L m−2 h−1 bar−1), respectively. Inclusion of the porous additives also enhanced membrane stability, demonstrated by 300 h of continuous OSN operation. These membranes showed improved molecular weight cut-off (MWCO) and significant potential in the separation of active pharmaceutical ingredients (APIs), including the almost complete rejection of Vitamin B12 in methanol. This work demonstrates that the facile production of ultrathin membranes using intrinsically microporous polymers is possible, enabling these exciting membrane materials to be considered for industrial applications.

Direct analysis of chiral active pharmaceutical ingredients and their counterions by ultra high performance liquid chromatography with macrocyclic glycopeptide-based chiral stationary phases

In this work the simultaneous separation of chiral active pharmaceutical ingredients (API) in salt form from their counterions has been performed by using different high-efficiency macrocyclic glycopeptide-based chiral stationary phases (CSPs). Not only a new zwitterionic vancomycin-based CSP has been prepared (similarly to what was done for teicoplanin) but macrocyclic selectors have also been bonded to sub-2 μm fully porous silica particles through traditional ureidic linkage to obtain versions of CSPs suitable for ultra-high performance applications. The direct separation of chiral APIs and counterions is particularly attracting since it simplifies the workflow traditionally used with reduction of analysis time and costs. The wide selection of macrocyclic antibiotics CSPs now available has allowed to manage different cases that can happen in the simultaneous separation of APIs and their counterions (either cations or anions). Indeed, while inorganic cations are retained on traditional vancomycin- and teicoplanin-based CSPs, inorganic anions are almost unretained (due to Donnan’s effect). On the other hand, cations and anions can be both retained on the zwitterionic versions of these CSPs. Afterwards, zwitterionic CSPs allowed the separation of other compounds including N-derivative amino-acids, profens, polyols, sugar anomers, oligosaccharides and inorganic anions/cations opening new perspectives in the use of this family of CSPs.

Characterization of Phase Separation Propensity for Amorphous Spray Dried Dispersions.

A generalized screening approach, applying isothermal calorimetry at 37 °C 100% RH, to formulations of spray dried dispersions (SDDs) for two active pharmaceutical ingredients (APIs) (BMS-903452 and BMS-986034) is demonstrated. APIs 452 and 034, with similar chemotypes, were synthesized and promoted during development for oral dosing. Both APIs were formulated as SDDs for animal exposure studies using the polymer hydroxypropylmethlycellulose acetyl succinate M grade (HPMCAS-M). 452 formulated at 30% (wt/wt %) was an extremely robust SDD that was able to withstand 40 °C 75% RH open storage conditions for 6 months with no physical evidence of crystallization or loss of dissolution performance. Though 034 was a chemical analogue with similar physical chemical properties to 452, a physically stable SDD of 034 could not be formulated in HPMCAS-M at any of the drug loads attempted. This study was used to develop experience with specific physical characterization laboratory techniques to evaluate the physical stability of SDDs and to characterize the propensity of SDDs to phase separate and possibly crystallize. The screening strategy adopted was to stress the formulated SDDs with a temperature humidity screen, within the calorimeter, and to apply orthogonal analytical techniques to gain a more informed understanding of why these SDDs formulated with HPMCAS-M demonstrated such different physical stability. Isothermal calorimetry (thermal activity monitor, TAM) was employed as a primary stress screen wherein the SDD formulations were monitored for 3 days at 37 °C 100% RH for signs of phase separation and possible crystallization of API. Powder X-ray diffraction (pXRD), modulated differential scanning calorimetry (mDSC), Fourier transform infrared spectroscopy (FTIR), and solid state nuclear magnetic resonance (ssNMR) were all used to examine formulated SDDs and neat amorphous drug. 452 SDDs formulated at 30% (wt/wt %) or less did not show phase separation behavior upon exposure to 37 °C 100% RH for 3 days. 034 SDD formulations from 10 through 50% (wt/wt %) all demonstrated thermal traces consistent with exothermic phase separation events over 3 days at 37 °C 100% RH in the TAM. However, only the 15, 30, and 50% containing 034 samples showed pXRD patterns consistent with crystalline material in post-TAM samples. Isothermal calorimetry is a useful screening tool to probe robust SDD physical performance and help investigate the level of drug polymer miscibility under a humid stress. Orthogonal analytical techniques such as pXRD, ssNMR, and FTIR were key in this SDD formulation screening to gain physical understanding and confirm or refute whether physical changes occur during the observed thermal events characterized by the calorimetric screening experiments.

Separation of Active Pharmaceutical Ingredients (APIs) from Excipients in Pharmaceutical Formulations

The active pharmaceutical ingredient (API) may be physically separated from the excipients in a pharmaceutical formulation by making use of the difference in density of the API and that of the excipients. The API may then be fully characterized by standard techniques. In the density separation process, the API is not dissolved, and the crystal form of the API is not changed. As examples, Form I fexofenadine hydrochloride is separated from Allegra Allergy 24 h Tablets, and Form I lansoprazole is separated from Equate Lansoprazole Delayed Release Capsules.

An Overview of HPLC Methods for the Enantiomer Separation of Active Pharmaceutical Ingredients in Bulk and Drug Formulations

An Overview of HPLC Methods for the Enantiomer Separation of Active Pharmaceutical Ingredients in Bulk and Drug Formulations

Investigations on air induced segregation of pharmaceutical powders and effect of material flow functions

For the pharmaceutical industry, powder segregation can occur in many processes such as blending and compression solid dose unit operations. Yet it is important that the high quality standards of drug product manufacture are maintained throughout the whole processes. Powder segregation has been identified by the pharmaceutical industry as a potential issue, and in some cases it may cause variability in tablet assay and uniformity throughout a compression run. Early studies suggested for certain Direct Compression (DC) products, the separation of Active Pharmaceutical Ingredient (API) from excipients could arise due to air-induced segregation of the powders discharging from an Intermediate Bulk Container (IBC) to the tablet press via a vertical chute. Segregation tests were carried out on trial powder blend materials supplied by GlaxoSmithKline (GSK), using a laboratory-scale air elutriation test facility at The Wolfson Centre. Particle size analysis of the virgin and segregated sub-samples clearly indicated that powder segregation occurred as a result of aerodynamic effects. Subsequent chemical assay results concurred with the particle size results. Flowability testing of the powder blends indicated them to be free-flowing materials; this in addition to the presence of large particle size differentials within the powder blends is the likely cause of the susceptibility to air-induced segregation.

The effect of drift gas on the separation of active pharmaceutical ingredients and impurities by ion mobility–mass spectrometry

The effect of drift gas and binary gas mixtures on the separation of active pharmaceutical ingredients and related compounds has been investigated for the first time using tri-wave ion mobility–mass spectrometry. The drift times for [M+H] + ions were measured in argon, carbon dioxide, nitrogen, helium and binary mixtures of these gases as a function of pressure and drift gas composition. At the same drift cell pressure the drift times of the protonated ions decreased in order; carbon dioxide > argon > nitrogen > helium. The drift times of compounds in the different drift gases were dependent on the polarizability of the drift gas, the size of the drift gas and the reduced mass of the analyte ion/drift gas pair. Resolution of the active pharmaceutical ingredients Lamotrigine and Rosiglitazone increased with drift cell pressure for argon and nitrogen, but showed no significant increase in carbon dioxide. Enhanced selectivity is demonstrated for the separation of pharmaceutical components using binary drift gas mixtures in tri-wave IM–MS.