Application of a newly developed portable NIR imaging device to monitor the dissolution process of tablets

We have recently developed a novel portable NIR imaging device (D-NIRs), which has a high speed and high wavelength resolution. This NIR imaging approach has been developed by utilizing D-NIRs for studying the dissolution of a model tablet containing 20 % ascorbic acid (AsA) as an active pharmaceutical ingredient and 80 % hydroxypropyl methylcellulose, where the tablet is sealed by a special cell. Diffuse reflectance NIR spectra in the 1,000 to 1,600 nm region were measured during the dissolution of the tablet. A unique band at around 1,361 nm of AsA was identified by the second derivative spectra of tablet and used for AsA distribution NIR imaging. Two-dimensional change of AsA concentration of the tablet due to water penetration is clearly shown by using the band-based image at 1,361 nm in NIR spectra obtained with high speed. Moreover, it is significantly enhanced by using the intensity ratio of two bands at 1,361 and 1,354 nm corresponding to AsA and water absorption, respectively, showing the dissolution process. The imaging results suggest that the amount of AsA in the imaged area decreases with increasing water penetration. The proposed NIR imaging approach using the intensity of a specific band or the ratio of two bands combined with the developed portable NIR imaging instrument, is a potentially useful practical way to evaluate the tablet at every moment during dissolution and to monitor the concentration distribution of each drug component in the tablet.

Pressure-induced variation of cellulose tablet studied by two-dimensional (2D) near-infrared (NIR) correlation spectroscopy in conjunction with projection pretreatment

Projection two-dimensional (2D) correlation analysis, achieved by selectively eliminating specific portion of dynamic spectra synchronized with the projecting vector, was used to study compression-induced variation of cellulose tablet monitored by near-infrared (NIR) spectroscopy and water sorption test. The increased density of the tablet by compression provided apparent variation of spectral intensity much larger than those caused by the change in the cellulosic structure. The direct calculation of 2D NIR correlation spectra from the raw spectra generated a relatively uninformative synchronous correlation spectrum and a very noisy asynchronous correlation spectrum due to the predominant intensity variation arising from the light scattering. In contrast, significant correlation features were elucidated without being hampered by the baseline fluctuation when the projection-corrected NIR spectra were constructed by the projection onto the space spanned orthogonal to the baseline change. Fine features of the compression-induced variation of the system were also elucidated by 2D hetero-correlation analysis based on the NIR spectra and water sorption profiles. The 2D correlation analysis revealed that the compression produces a disordered amorphous component of cellulose. The development of mobile amorphous phase results in a more tightly packed matrix with less porosity, which in turn prevents the penetration of water into the tablet and delays the water sorption.     

Qualitative Discrimination Between Paracetamol Tablets Made by Near Infrared Spectroscopy and Chemometrics With Regard to Polymorphism

Polymorphism is an important characteristic of pharmaceutical products because different polymorphs exhibit different physicochemical stabilities, dissolution rates, etc., which makes them different in therapeutic efficiency. Thus, it is important to control the polymorphic structure of pharmaceutical products. A spectroscopy method based on Fourier transform near infrared (FT-NIR) spectroscopy and chemometric techniques is introduced to classify paracetamol preparations according to polymorphic changes. X-ray diffraction (XRD) and FT-NIR studies were carried out on standard samples, paracetamol preparations (acetaminophen tablet), and also the additives. A direct comparison was performed between the spectroscopic data and those obtained by XRD. The NIR and XRD analyses of paracetamol preparations show some distinct differences, particularly in the Iranian tablet. These differences are found to be related to polymorphism and paracetamol purity. The cluster analysis (CA) and principal component analysis (PCA) were utilized to classify the paracetamol preparations. FT-NIR spectroscopy provides a simple, rapid and accurate qualitative analysis method for the identification of paracetamol polymorphs.     

Influence of internal structure on kinetics of drug release from wax matrix tablets

To examine the influence of the internal structure of a wax matrix tablet on in vitro drug release, the release rates of several tablets consisting of various proportions of drug and wax were compared with the water penetration rates from the compressed and lateral surfaces of the tablets. The penetration rates from the lateral surface were found to be much faster than those from the compressed surface in all cases. A theoretical equation involving a two-dissolving-direction was derived on the basis of the boundary retreating concept. The retreating rate constants deduced from the dissolution results were well coincident with the values directly determined by the needle penetration method, suggesting good applicability of the proposed equation. The results suggest that the tortuosity of the water channels created in a tablet during dissolution is generally smaller in the horizontal direction than that in the vertical direction. This would be caused by the drug particles or granules being elongated in the horizontal direction by compression.     

Formulation approach for nicorandil pulsatile release tablet

The purpose of this study was to obtain a nicorandil pulsatile release tablet that has a well-regulated release lag time. When nicorandil is used as an antiangina drug, administration time control is important. A pulsatile release tablet is one of the effective approaches to modified release to reduce daily administration frequency. In this study, a pulsatile release tablet of nicorandil was formulated by fumaric acid dry coating around the core tablet including nicorandil. The model tablets, which had different content ratios of excipients in the dry-coating layer, were characterized by a dissolution test. The results showed that the release lag time was generated with fast release profiles. Various lag time controls of tablets were achieved, from 60 to 310 min on average, by variation of outer layer composition. From an analysis of the relation between lag times and outer layer composition, the key ingredient for prolongation of lag time was found to be fumaric acid. To analyze the lag time generation mechanism, water penetration for tablet was measured. The results indicated that the penetration depth was proportionate to the square root of time and the lag time formation mechanism was simple water penetration through the matrix of fumaric acid to the tablet core. The results also showed that the Washburn equation could be used to design the lag time of the pulsatile release tablet in this study. In conclusion, novel release control technology using fumaric acid was appropriate to obtain a nicorandil pulsatile release tablet that has well regulated lag time.     

On-line determination and control of the water content in a continuous conversion reactor using NIR spectroscopy

On-line near infrared spectroscopy was used to determine the water content in a continuous conversion reactor. The NIR predictions were incorporated into the distributed control system (DCS) which then controlled the addition of water to the reactor. The conversion reaction utilizes methanol, water, sodium carbonate and a reactant. Control of the water content is important for a number of reasons. At elevated water levels, a competing hydrolysis reaction increases along with the product solubility in the mother liquor leading to product losses. At reduced water levels, the product becomes anhydrous and the reaction mixture becomes gelatinous, necessitating a shutdown of the reactor for cleaning. The previous procedure for monitoring water was to remove a sample once per hour, transfer the sample to the laboratory, and run a Karl Fisher assay. Upon obtaining results from the lab, an operator would manually adjust the water inlet valve to the reactor. NIR spectroscopy in an on-line mode allows spectra to be collected every 200 s markedly increasing the frequency of results. A partial least squares model was constructed, validated and successfully implemented to predict the water content of the reactor. Further, by feeding the results to the process DCS, water additions to the reactor were fully automated. The increased frequency of sampling by NIR led to an improvement in the control of the water content and decreased the normal amount of equipment downtime. These factors improved process stability and recovery thereby generating an estimated $500,000 in savings over the course of the campaign.     

Application of polyglycolized glycerides in protection of amorphous form of etoricoxib during compression

Polymorphic transition and stability problems during amorphous drug formulation are the major limiting factors in pharmaceutical technology. The purpose of the study was to evaluate the ability of polyglycolized glycerides (Gelucire) in protection of amorphous form of drug during compression and shelf life with lower proportion. Amorphous etoricoxib (AET) was prepared by spray drying technique. Tablets of AET and melt granules of AET (MG-AET) with Gelucire 50/13 were prepared. Tablets parameters like hardness, disintegration and content uniformity were evaluated. Tablets were evaluated immediately after compression and on storage for 3 months at ambient conditions to determine degree of transformation using X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and dissolution profiles. Spray drying yielded the amorphous etoricoxib. Content uniformity in the tablet was in between 95 to 105%. Other parameters like disintegration and hardness were well within the limits. The results showed significant difference in the degree of crystallinity between AET tablet and MG-AET tablet. MG-AET tablet showed absence of crystallinity after 3 months storage. The reason could be formation of hydrogen bonding between the Gelucire and AET. Also Gelucire can be tableted very easily under low pressure and showed elastic recovery. Gelucire yielded a soft embedding during tableting, which prevented the polymorphic transformation. Polyglycolized glycerides (Gelucire 50/13) are able to protect amorphous etoricoxib during compression. As excipient required is low, it became possible to prepare tablet formulation as compared to other excipient like polyvinylpyrrolidon (PVP).     

ICA方法与NIR技术用于药片中活性成分含量的测定

用独立分量分析(ICA)方法提取药片近红外光谱数据矩阵的独立成分和相应的混合矩阵, 再用BP神经网络对混合矩阵和药片中活性成分的浓度矩阵进行建模, 提出了新的药片活性成分含量测定的基于独立分量分析-神经网络回归(ICA-NNR)的近红外光谱分析方法. 通过分析独立分量数和网络中间隐层的神经元数对模型性能的影响, 分别建立三类药片定量分析的最优模型. 该方法用于实测的三类药片中活性成分含量的测定, 测试样品集的化学检测值与近红外预测值的相关系数分别达到0.962, 0.980及0.979. 结果表明, 基于ICA-NNR的近红外光谱分析方法对制药业的药片进行定量分析是可行的.     

Thermal,spectroscopic, and dissolution studies of ketoconazole–Pluronic F127 system

One strategy for improving the dissolution of poorly water soluble drugs is to prepare solid dispersions such as binary mixtures with hydrophilic carriers. These mixtures are generally characterized by better solubility than those of the individual components from which they are formed. In the present study, solid dispersions of ketoconazole (KET) with Pluronic F127 (PLU) were prepared by the grinding method. Solid–liquid equilibria in the system being studied were investigated by differential scanning calorimetry. A phase diagram for the whole range of compositions was constructed. The investigation revealed that ketoconazole and Pluronic F127 form a simple eutectic system containing 4.4 % w/w of ketoconazole at the eutectic point. The results of Fourier transform infrared spectroscopy and X-ray powder diffractometry studies of obtained mixtures suggest that there is no drug-carrier interaction and both components are crystalline in the solid dispersion with the whole range of composition. The prepared mixtures show an appreciable improvement of the dissolution rate of KET in 0.5 % w/v sodium lauryl sulfate. The improvement of the dissolution rate of drug is additionally increased by effective solubilization.     

Application of nilvadipine solid dispersion to tablet formulation and manufacturing using crospovidone and methylcellulose as dispersion carriers

Nilvadipine (NIL) solid dispersion using crospovidone (Cross-linked-N-vinyl-2-pyrolidone, cl-PVP) and methylcellulose (MC) as carriers was applied to tablet formulation. Several grades of cl-PVP and MC were used, and their influence on tablet properties such as hardness, disintegration, dissolution and chemical stability were investigated. The agitation granulation method was used for preparation of solid dispersion granules, and the granules were compressed using a rotary tableting machine, and finally the obtained tablets were coated with film. As the particle size of cl-PVP decreased, hardness and apparent solubility were increased, while dissolution rate was lowered. When a higher viscosity grade of MC was used, hardness and dissolution rate were increased, and apparent solubility did not change. All batches of tablets were chemically stable at 40 degrees C, 75% relative humidity (R.H.) for six months. Finally, tablets with enhanced dissolution properties were obtained by using Polyplasdone XL-10 and Metolose SM-25 as the grades of cl-PVP and MC, respectively. These formulation tablets showed higher solubility and dissolution rate during storage as well as initial indicating good physical stability.     

Solution properties and solvatochromism of bis(<Emphasis Type="Italic">N</Emphasis>-2-pyridyl-salicylaldiminato)cobalt(II)

The bis(N-2-pyridyl-salicylaldiminato)cobalt(II) complex ([Co(sap)₂]), a reddish-pink crystalline compound has been characterized by elemental analysis, molar conductivity, cyclic voltammetry, and Vis–NIR spectroscopy. Combination of all techniques indicates a tetrahedral geometry for the complex in solid state and in the solvents used. Electronic spectroscopy was used to determine the ligand–field parameters as well as chromaticity coordinates; for discrimination of color changes CIE and CIELAB color spaces have been applied.     

Near-infrared spectroscopy of autunites

NIR spectroscopy has been applied to the study water in the interlayer of the autunite minerals. The spectra of autunites and metaautunites in the first HOH fundamental overtone are different and the spectra of autunites of different origins in the 6000-7500 cm(-1) region are considerably different. A number of conclusions are made based upon the NIR spectra: (a) The spectra of different autunites are different in the NIR spectral region; (b) the spectra of metaautunites show similarity; (c) the spectra of metaautunites are different from that of autunites. NIR spectroscopy provides a method of determination of the structure of water in the interlayer of natural autunites. The implication from the variation in the NIR spectra is that the structural arrangement of water for different autunites is different and is sample dependent. NIR spectroscopy has a wide potential for the study of the autunite minerals.     

Design and preparation of pulsatile release tablet as a new oral drug delivery system.

To achieve time-controlled or site specific delivery of a drug in the gastrointestinal tract, an orally applicable pulsatile drug release system with the dry-coated tablet form was developed. The system consisted of a less water permeable outer shell and a swellable core tablet; from such a system, the drug was expected to be rapidly released after a certain period of time on the basis of time-controlled disintegration mechanism. Various model disks of outer shell, consisting of hydrogenated castor oil and polyethyleneglycol 6000, were tested for their water penetration rate. The experimental results showed that water penetration proceeded obeying the boundary retreating mechanism, so that the lag time of the system could be controlled by changing either the thickness or the composition of the outer shell. The swelling force of various commercially available disintegrants was quantitatively compared, and it was found that carboxymethylcellulose calcium was the preferable disintegrant to be used for the core tablet. On the basis of the results of a series of fundamental studies, various pulsatile release tablets of isoniazide with different lag times were designed. In the in vitro dissolution test, typical pulsatile release was achieved for all the tablets prepared, and a good correlation was found between the observed lag time and the estimated lag time calculated from an empirical equation deduced from the thickness and polyethyleneglycol 6000 content of the outer shell.     

中药口服固体制剂原辅料近红外光谱数据库的构建及应用

建立了中药口服固体制剂原辅料近红外(NIR)光谱数据库,采用模式识别方法研究了NIR光谱数据在物料分类和物性预测中的应用。使用便携式近红外光谱仪快速测量149批原辅料粉末的NIR漫反射光谱数据,并录入iTCM数据库。利用主成分分析(PCA)法探究NIR光谱数据对已知结构物料的分类能力,采用偏最小二乘(PLS)法研究了NIR光谱对原辅料物性参数和直接压片片剂性能的预测能力。经标准正态变量变换(SNV)+Savitzky-Golay(SG)平滑+一阶导数处理后的NIR光谱数据对微晶纤维素、乳糖、乙基纤维素、交联聚维酮和羟丙基甲基纤维素这5类辅料的区分能力较好。NIR光谱数据与原辅料粉末粒径、密度和吸湿性的相关性较强。NIR光谱信息作为物料物理性质的补充,可提高粉末直接压片片剂性能预测模型的性能。NIR光谱数据是iTCM数据库物性参数数据的补充,物性参数与NIR光谱数据的结合能更全面地表征原辅料的性质。     

High-throughput study of phenytoin solid dispersions: formulation using an automated solvent casting method, dissolution testing, and scaling-up

A high-throughput experimentation method for studying the dissolution of phenytoin, a poorly water soluble drug, was developed and validated. Solid dispersions with 12 excipients (7 polymers and 5 surfactants) were prepared and tested. Each excipient was screened with three drug loadings: 10, 20, and 40% (w/w). Each solid dispersion was prepared in triplicate, for a total of 108 samples. The drug dissolution was studied in simulated gastric fluid without pepsin plus 1% sodium laurylsulfate. This study led to the identification of three improved formulations, exhibiting an extent of dissolution higher than 90% after both 30 and 60 min. The HTE results could be reproduced at a larger scale using a conventional solvent evaporating method, proving the reliability of the HTE protocol.     

Thermal, spectroscopic, and dissolution studies of the simvastatin–acetylsalicylic acid mixtures

The objective of the present investigation was to study the effect of eutectic formation on in vitro dissolution of simvastatin (SIM) released from mixtures with acetylsalicylic acid (ASA) prepared by a grinding method. SIM–ASA mixtures were characterized by means of differential scanning calorimetry (DSC), infrared spectroscopy (IR), X-ray powder diffractometry (XRPD), and in vitro dissolution tests. IR spectroscopy and XRPD studies indicated no interaction between SIM and ASA in the solid state. The DSC investigation has revealed that SIM and ASA form a simple eutectic system containing 66.6 % w/w of SIM at the eutectic point. In vitro dissolution studies of SIM and its mixtures with ASA were carried out. The eutectic mixture shows an appreciable increase in the dissolution rate in comparison with other ratios and SIM in 0.5 % w/v sodium lauryl sulfate. The dissolution enhancement of SIM was related to the effective wetting of the drug particles with a significantly reduced size released from eutectic composition. In conclusion, dissolution of SIM can be enhanced through eutectic formation with ASA by means of simple mechanical activation (a grinding method).     

Study of the temperature-dependent near-infrared spectra of water by two-dimensional correlation spectroscopy and principal components analysis

Near-infrared spectroscopy (NIR) is an important analytical tool in monitoring properties of systems for that water is a major constituent. For such objects of analysis a quality of information extracted from the NIR spectra depends essentially on used methods of analysis of a massive absorbance of water. Correctly chosen method should be able to identified rational number of overlapped components hidden under the broad band of water. The resolved components have to be justified on grounds of the structure of water and by relation to the properties a hydrogen-bonded network of water molecules. The interest in the correlation is imposed by a fact that hydrogen bonds of water around nonpolar group are significantly strengthened and weakened around polar groups. Intensity variations classified in this context could be valuable source of information on varying properties of the solute molecules embedded in water environment. Therefore, there is a big interest in methods that have a power for detailed analysis of the intensity changes in the broad NIR spectra. Two-dimensional correlation spectroscopy (2DCOS) and principal component analysis (PCA) are our proposition. In the analysis of the temperature-dependent NIR spectra of water by means of the two methods we have focused on the interpretation of the 2DCOS results through the concept of linear and nonlinear relationships. Moreover, a cascaded curve fitting procedure has been employed. Presented approach should be very instructive of how to interpret the features of the 2D results that frequently is not a straightforward task.     

Preparation and physicochemical characterization of carbamazepine (CBMZ): para-sulfonated calix[n]arene inclusion complexes

The formation of inclusion complexes with para-sulfonated calix[n]arene (PSC[n]A) was studied for carbamazepine (CBMZ), a poorly water soluble anticonvulsant drug. The effect of PSC[4]A and PSC[6]A on aqueous solubility of carbamazepine was studied extensively. The complete complexation of the drug was achieved after 48 h of shaking with PSC[n]A in water and evaporation of water to get solid complex. The interaction between PSC[n]A and CBMZ in solid state inclusion complexes was accomplished by aqueous phase solubility studies, HPLC, DSC, PXRD, FTIR, UV–Vis, and FT-Raman spectroscopy. The solubility of CBMZ increases as a function of PSC[n]A concentration. The results of the two phase solubility experiments are in good conformity to signify the formation of 1:1 (PSC[6]A:CBMZ) and 2:1 PSC[4]A:CBMZ complexes. The order of dissolution rate of CBMZ is inclusion complex > physical mixture > drug alone. The purpose of this study was to enhance solubility resulting in high dissolution rate and bioavailability of this essentially water insoluble drug.     

Qualitative and quantitative analysis of oxytetracycline by near-infrared spectroscopy

Near-infrared (NIR) spectroscopy, in combination with chemometrics, enable the analysis of raw materials without time-consuming sample preparation methods. The aim of our work was to estimate critical parameters in the analytical specification of oxytetracycline, and consequently the development of a method for quantification and qualification of these parameters by NIR spectroscopy. A Karl Fischer (K.F.) titration to determine the water content, a colorimetric assay method, and Fourier transform-infrared (FT-IR) spectroscopy to identify the oxytetracycline base, were used as reference methods, respectively. Multivariate calibration was performed on NIR spectral data using principal component analysis (PCA), partial least-squares (PLS 1) and principal component regression (PCR) chemometric methods. Multivariate calibration models for NIR spectroscopy have been developed. Using PCA and the Soft Independent Modelling of Class Analogy (SIMCA) approach, we established the cluster model for the determination of sample identity. PLS 1 and PCR regression methods were applied to develop the calibration models for the determination of water content and the assay of the oxytetracycline base. Comparing the PLS and PCR regression methods we found out that the PLS is better established by NIR, especially as the spectroscopic data (NIR spectra) are highly collinear and there are many wavelengths due to non-selective wavelengths. The calibration models for NIR spectroscopy are convenient alternatives to the colorimetric method and to the K.F. method, as well as to FT-IR spectroscopy, in the routine control of incoming material.     

Near-infrared spectroscopy of torbernites and metatorbernites

A suite of torbernites and metatorbernites have been analysed by near-infrared spectroscopy. The spectra of torbernites and metatorbernites in the first HOH fundamental overtone are different and the spectra of torbernites of different origins in the 6000-7500 cm(-1) region vary. NIR spectroscopy provides a method of studying the hydration of cations in the interlayer of torbernite. NIR spectroscopy shows that the spectra of torbernites from different origins in the water HOH first fundamental overtone and combination regions are different. This difference implies the hydration of cations is different for torbernite minerals. The structural arrangement of the water molecules in the interlayer is sample dependent. The NIR spectra of metatorbernites are different from that of torbernites and a similarity of the spectra of metatorbernites suggests that the water structure in metatorbernites is similar.