Study progression in application of process analytical technologies on f i lm coating

Tingting Peng,Ying Hung,Liling Mei,Linn Wu,Longki Chen, Xin Pn,＊,Chunbin Wu,b

aSchool of Pharmaceutical Sciences,Sun Yat-Sen University,Guangzhou 510006,ChinabGuangdong Research Center for Drug Delivery Systems,Guangzhou 510006,China

Review

Study progression in application of process analytical technologies on f i lm coating

Tingting Penga,Ying Huanga,Liling Meia,Linna Wua,Longkai Chena, Xin Pana,＊,Chuanbin Wua,b

aSchool of Pharmaceutical Sciences,Sun Yat-Sen University,Guangzhou 510006,ChinabGuangdong Research Center for Drug Delivery Systems,Guangzhou 510006,China

ARTICLEINFO

Article history:

Received 27 July 2014

Received in revised form

10 October 2014

Accepted 11 October 2014

Available online 23 December 2014

Film coating

Film coating is an important unit operation to produce solid dosage forms,thereby,the monitoring of this process is helpful to f i nd problems in time and improve the quality of coated products.Traditional methods adopted to monitor this process include measurement of coating weight gain,performance of disintegration and dissolution test,etc. However,not only do these methods cause destruction to the samples,but also consume time and energy.There have recently emerged the applications of process analytical technologies(PAT)on f i lm coating,especially some novel spectroscopic and imaging technologies,which have the potential to real-time track the progress in f i lm coating and optimize production eff i ciency.This article gives an overview on the application of such technologies for f i lm coating,with the goal to provide a reference for the further researches.

©2015 Shenyang Pharmaceutical University.Production and hosting by Elsevier B.V.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/ licenses/by-nc-nd/3.0/).

1.Introduction

In the f i eld of industrial manufacturing,the implementation of real-time analysis of products,holds great signif i cance for both the management and optimization of the whole production process,as well as the improvement in product quality.In the past few decades,the application of process analytical technologies(PAT)to monitor pharmaceutical unit operation has drawn more and more attention.PAT is the key elementofthe“21stcenturymedicinecurrentgood manufacturing practices-based on risk”initiative,which is issued by FDA[1,2].Theprimary goal of the implementation of PAT for f i lm coating is“process understanding,optimization of manufacturing eff i ciency,improvement of product quality and reproducibility”[3].More specif i cally,the application of PAT on f i lm coating is ref l ected in these aspects:(1)measurement of average amount of coating and average coating thickness on tablets/pellets[4],(2)determination of coating uniformity and process endpoint[5],(3)provision of information on coating uniformity/variability within the inter-orintra-tablet[4],(4)plotting of coating structure[6].Coated products are generally used as fi nal products of the solid dosage forms,thereby their quality will more or less affect the speci fi c performance of the active pharmaceutical ingredients (API).In most cases,a certain amount of coating thickness and uniformity is imperative to maintain the quality,stability and security of the solid dosage forms,which is associated with functionalities,including desired amount of drug released at the speci fi c site,masking unpleasant taste or odor,improving esthetic appearance of a drug product,etc.Therefore the monitoring of these parameters during coating process is in urgent need.Traditional methods used to monitor these parameters are to collect limited samples from a coating pan or a fl uidized bed at interval time,while the implementation of PAT can achieve the goal of real-time analysis of the coating process.PAT offer major advantages over the traditional methods in the acquirement of analytical data and the time used to monitor the coating process.Within the PAT framework,process data can be collected during the whole progress of a coated product and a considerably larger fraction of sample units could be analyzed during manufacturing,thus providing more insight into the process and greater con fidence in the quality of the fi nal product[3].

The performed measurements by process analysis can be classi fi ed into four types[7]:in-line,no removal of the sample; on-line,sample is diverted from the main process,analyzed and may be returned;at-line,sample is removedand analyzed closed to the process;off-line,sample is removed and analyzedawayfromtheprocess.Comparedtoat-line methods,result obtained by in-line or on-line measurements should be markedly faster.It is hard to de fi ne the difference between at-line and off-line measurement in lab scale processing,because coating equipment and analytical procedure often take place in the same lab.

PAT can avoid the disadvantages of traditional coating monitoring methods,such as measurement of coating weight gain(gravimetric method),though it is a rapid and currently the most widely used evaluation methods[8],it does not provide information regarding the coating material and coating uniformity,and neglect the ruptures of core material and the accuracy of the results due to the different mass loss within the samples during drying/curing process[1].However, the disintegration time limit or in vitro dissolution method, dose not only cause destruction to the samples,but furthermore consume time and energy[9].Additionally,PAT can be used for real-time monitoring and acquisition of data information from a large amount of samples through the entire coating progress,which is helpful to fully understand the coating process and provide more reliance on the quality of the fi nal product[3].Thus,it is speculated that there is a great potentialin the application of PAT on fi lm coatingaccordingto the principles of quality by design(QbD).The currently reported techniques used as PAT to monitor the coating process include:(1)spectroscopic techniques,such as near infrared spectrum(NIRS)[8,10],Raman spectroscopy[3,11],laser induced breakdown spectroscopy(LIBS)[12-14];(2)imaging techniques,such as terahertz pulse imaging(TPI)[15,16],near infrared imaging[1],magnetic resonance imaging(MRI)[17]; (3)microscopic techniques,such as confocal laser scanning microscope(CLSM)[6],atomic force microscope(AFM)[6], scanning electron microscope(SEM)[1,6],etc.Since the microscopic techniques tend to destroy samples,they are not suitable for online analysis and the present studies focus more on spectroscopic and imaging techniques.This article mainly discussed the development of these two techniques for f i lm coating.

2.Access to establish process analytical technologies(PAT)

The implementing process analyzers into coating process streams can be realized mainly through the following steps (Fig.1).For the coating of tablets,it is commonly performed in a pan coater,while for the coating of pellets,it is generally done in a f l uidized bed to reduce adhesion of the particles during coating.To successfully and accurately monitor the coating process,some aspects should be considered[18].First, a suitable process analyzer or combination of complementary process analyzers should be selected according to the attributes of the measured samples to monitor the desired critical process and product information.Then,it is necessary to determine the locations in the process streams where and how process analyzers should be and can be implemented to monitor the required information,as the location of the process analyzer in the equipment is a critical factor.Here,a NIR probe is taken as an example[19].In drum coaters it is usually mounted above the moving tablet bed in a position where no spray liquid can hit the measuring window.When an immersion probe is used fouling can be prevented by purging theprobe with gas.In f l uidized bed equipment the probe can be integrated in the cylinder wall.Fouling seems to be a minor problem in this case.Afterward,the optimal measurement conditions for the process analyzer should be determined to obtain useful data and establish a good correlation between data information and measured contents,such as average weight gain of the product or the amount of coated ingredient at each time interval[9,11],coating thickness[20],or coating times[21,60].Since f i lm coating is a multivariate unit operation with various process parameters,i.e.spray rate,inletand exhaust air temperature,inlet-and exhaust air f l ow,atomization air pressure,pan speed and gun to bed distance[4], it is not an easy task to model and predict the characteristics of the coated products.To minimize the inf l uence of processing variables,some mechanistic or physical models are often invoked for quantitative calibration and explanation of correlation between spectroscopic variables and response variables[20,57],such as principal component analysis(PCA) [4],partial least squares(PLS)[11,20],net analyte signal(NAS) [21],classical least squares(CLS)[20],target factor analysis (TFA)[20],discrete element method(DEM)[21],etc.Finally, validation of the performance of process stream analyzers is performed in designed batches.

3.Spectroscopic techniques

3.1.Near infrared spectroscopy(NIRS)

According to ASTM,near-infrared light is referred to as the electromagnetic wave whose wavelength falls between visible light and infrared region,namely,the wavelength in the range of 780-526 nm(Fig.2).A majority of substances in nature are abundant in absorption peak or emission peak in this wavelength range.The quantitative or qualitative analysis of these substances can be carried out by NIRS depending on the characteristic absorption peak intensity of the measured substances.NIRS is regarded as one of the most widely used and promising PAT.The interest in NIRS lies in its advantages over alternative instrumental techniques:(1)it can be used for qualitative evaluation of the samples by clustering principle, and quantitative assessment of the samples by multivariate calibration method and the established quantitative model based on the known properties or constitutes of the samples; (2)itis a rapidanalyticaltool withhigh output,and suitable for analysis of multiple complex components;(3)it requires minimal or no sample preparation with low cost analysis[22]; (4)it does not destroy samples,consume reagent and pollute the environment,which makes it a“green analytical technology”[23];(5)there is no demand for the physical status of the samples,whether they are in the status of gas,liquid or solid, qualitative/quantitative analysis is available;(6)the introduction of optical fi ber enables the usage of NIRS extended to process analysis and remote analysis,concomitantly makes the design of spectrometer more miniaturization.

In the art of pharmaceutical coating,the performance of NIRS is mainly to quantify the coating process[11,24],such as determination of the coating thickness and coating end point, analysis of coating uniformity or variations.Table 1 shows the examples of monitoring of the coating process by NIRS.As shown in Table 1,NIRS has been applied off-line,at-line,and in-line in a fl uidized bed apparatus and in a pan coater.And the currently performed researches on the monitoring of coating process are primarily for tablets rather than pellets. Most of these researches on pellets were focused on establishing proper methodology,which was applied to analyze coating thickness or coating thickness concerning drugrelease behavior.But Min JL and coworkers has pointed out that the combination of NIRS and laser diffraction particle size analyzer or confocal laser scanning microscopy can be used to accurately measure the coating thickness of the pellets based on partial least squares calibration model[32].NIR spectra were collected in real-time during the coating process via a fi ber-optic diffuse re fl ectance probe that was connected to the fl uid-bed coater,as shown in Fig.3.The major problem associated with measurement of pellet coating thickness by NIRS is poor correlation due to the differences in spectral information from dynamic fl uidized bed after statistical treatment[32].However,for the coating of tablets,the uneven distribution of tablets in a pan coater during coating processmay make changes in the sensitivity of the sensor,potentially leading to inaccurate analytical results[11].Lee and coworkers demonstrated that the average method could successfully circumvent the problems existing in the NIRS analytical technology and was the best way to predict coating thickness[33].

3.2.Raman spectroscopy

Both Raman spectroscopy and NIRS are molecular vibrational spectrumstudyingvibrationaltransitionsinmolecules [34,35].However,the analytical theory involved in them differs.The former is a sort of scattering spectrum,while the latter is a kind of absorption spectra.Raman scattering(Fig.2) can be obtained from the inelastic collision between the incident light photons from monochromatic light and molecular when the sample is exposed to light.Each substance has its own Raman spectra in feature.And it can be used to study the components and properties of the measured samples based on the unique frequency,intensity and polarization degree of spectrum.Also it is a complementary analytical tool to NIRS[17,36],as some chemical bonds with symmetrical charge distribution,such as C=C,S=S,whose infrared absorption is weak,can't be measured by infrared spectrometer, while the Raman spectrometer can well display the related information.Besides,it is suitable for the analysis of aqueous sample due to the weak absorption of water in Raman scattering.

As a novel analytical tool used for process monitoring, Raman spectroscopy has caused wide public concern over the global pharmaceutical industry[11].It is featured by sharp lines due to molecular vibrations,which makes it available for quantitative analysis of the coating process[9].The implementation of Raman spectroscopy in coating process is mainly used to determine drug contents and coating thickness,monitor drug polymorphic transformation and analyze coatinguniformity,etc.Somestatisticalmethodsare commonly adopted to analyze the results obtained from the Raman spectra.Romero-Torres and coworkers measured the coating thickness of colored tablet by means of Raman spectroscopy combined with univariate and multivariate data analysis[11].Besides,they employed partial least squares calibration model to quantify the variations within the tablets [24].ElHagrasyand coworkersdevelopedaquantitativemodel to predict the amount of tablet coating through the establishment of the correlation between Raman spectrum and average coating weight gain[37].In addition,they also used Raman spectroscopy combined with multivariate calibration model to determine coating uniformity,and the calibration model is verif i ed by tracking the coating progress of individual batches[9].The Raman spectrum used for real-time monitoring of the coating process possesses the following advantages[11]:(1)it is easy to document vibration spectrum,which provides signif i cant information on a complex mixture of components;(2)the integrity of measured samples could be maintained;(3)samples are allowed for no pretreatment;(4) remote analysis can be realized by collecting spectrum through optical f i ber;(5)spectroscopy analysis can be performed via complex pattern recognition technology.

Although the Raman spectroscopy technology used in the monitoring of coating process offers advantages,it has found limited use in practice for these and other applications due to the interfering fl uorescence(Fig.2),which is produced in many systems by the spontaneous emission of photos from low-lying excited electronic states[11].As the fl uorescence intensity is stronger than the Raman scattering intensity,the interfering fl uorescence can mask Raman spectrum of vibrational shifts,thus affecting accuracy of the results,especially encountered for colored samples under visible excitation.To overcome this limitation,spectroscopists commonly employ excitation resources in the near infrared region(NIR)where the illuminating source has insuf fi cient energy to reach most fl uorescence-producing excited electronic state[11].Additionally,when using Raman spectroscopy as an analytical tool to monitor the coating process,the analyst should be aware of thesenear infrared fl uorescentsubstances,such as iron oxide, which is often incorporated in tablet core as a colorant.

3.3.Laser-induced breakdown spectroscopy(LIBS)

LIBS is a novel analytical tool,with high-energy pulse plasma emission spectrum produced by the interaction between laser and material elements analysis of new technology.Local high temperature in the measured samples(solid,liquid,gas)was generated due to the irradiation by high-power pulsed laser, leading to the formation of plasma plumage after excitation or ionization of atoms and molecules in the samples.Part of the energy can be emitted in the form of light during the process of relaxation of the excited atoms and ions in plasma.The radiation can keenly ref l ect the characteristics of elements, therefore,qualitative and quantitative analysis of the chemical elements in the samplescan beperformedaccording to the recorded spectrum which contains the specif i c radiation signal[38].

TheLIBStechnologyhasbecomematureafterdevelopments of several decades,and related researches on it have inf i ltrated into more and more f i elds,such as soil composition,mineral,metal compounds,polymers,cosmetics,etc[13].However,there have been no reports in detail on the specif i c application of it in pharmaceutical industry. The currently reported applications of LIBS in the pharmaceutical industry include determination of excipients in the formulations[39,40],quantitative analysis of the API in solid dosage forms[41],evaluation of the distribution of magnesium stearate in the powder mixtures[42,43],investigation of the effect of physical properties of the samples on LIBS measurement[44],etc.

LIBS technology is featured by speed,which can allow it for online monitoring.Fig.4 shows the schematic representation of LIBS instrument[14].In the art of pharmaceutical coating,it can be used for on-line analysis of tablet coating thickness andcoatinguniformity.Moweryandcoworkershave demonstrated the potential of LIBS technology in rapid characterization of f i lm coating process[45].In addition,Madamba and coworkers developed a LIBS method to rapidly analyze the coating thickness and uniformity in tablet coating used for photoprotection,explored the photoprotection mechanism in the coated formulation by means of a novel approach for the quantitative determination of the coating depth prof i le,and evaluated the feasibility of using this tool as a method to determine photostability of the drug substance through comparison with the results obtained from high performance liquid chromatography(HPLC)method[14].Since the irradiation source used in LIBS is high-power pulsed laser,which generates a high local temperature in the measured samples, LIBS is a destructive analytical technology and not suitable in situations where samples needed to be reused[11,13].

4.Imaging techniques

The application of imaging techniques in the monitoring of coating process holds numerous superiorities:(1)data information can be obtained from multiple points of each sample, thus providing average information for the individual sample and reducing experimental error;(2)unlike the spectroscopy techniques,such as NIRS and Raman spectroscopy,it can realize depth detection of the samples;(3)compared with the results obtained from optical microscope,the analysis of coating uniformity is not only conf i ned to a few points,but extended to the whole tablet surface;(4)compared with the traditional monitoring methods,it can allow for rapid analysis without destruction to the measured samples,and is time-/ labor-saving.The currently reported imaging techniques for the monitoring of the coating process are displayed as following.

4.1.Terahertz pulsed imaging(TPI)

Terahertz is also referred to as far infrared,which spans from infrared to microwave in the electromagnetic spectrum,with the wavelength ranging from 30 μm to 3000 μm or from 100 GHz to 10 THz[1].Compared with other imaging techniques,TPItechnologyisremarkablyadvantageousin acquiring the amount of information.The acquired data set is actually three dimensional space-time data(three dimensional space axial(x,y)and one dimensional timeline).Terahertz images from a series of samples are available via these three dimensional data set[46].TPI is a non-destructive measurementtechnique,andcanbeusedtomeasure coating thickness on tablets.To measure the coating thickness,TPI works in this way[15],as shown in Fig.5:since the coating layer is translucent to terahertz radiation,when the short pulses of terahertz radiation(half maximum full width (FWHM)＜1 ps)are focused on the coating tablet surface,part of the pulse can penetrate into the coating layer,and the other part of the pulse is ref l ected back to the detector.Furthermore, part of the pulses is ref l ected back where the refractive index of each interface changes,and can be detected as an additional ref l ected pulse.The coated thickness can be calculated according to the equation 2 dcoat=Δt c/n,wherein t is the delay time between the two ref l ected pulse,c is the speed of light,n is the refractive index of coating materials.The detailed information about the TPI measurement technology is provided by Zeitler and coworkers[47].

TPItechnologyoffersmajoradvantagesoverother analytical techniques used to study f i lm coating,including:(1) compared with the LIBS technology,this technology is a completely non-invasive analytical tool,but possesses a similar depth resolution and a higher axial resolution[6];(2) the average energy generated by this technology during analysis is low,thus causing no thermal damage to the samples[16],and enabling samples to be reused for some functional researches[6];(3)any number of locations in the tablet can be probed by TPI,and the measurement can be extended to produce a three-dimensional map of the tablet.Meanwhile, the tablet uniformity can also be shown as a function of depth below the surface[6];(4)it can not only provide similar information to that of NIRS and Raman spectra,but also extract detailed information on coating thickness due to the mapping established in the whole tablet surface[16];(5)it is suitable for the analysis of single layer or multilayer complex coating due to the strong penetration capability of terahertz radiation, under the conditions where the coating thickness was more than 30 μm,which is associated with the measurement precision of this technology.

Since TPI is advantageous in many aspects,there is an increasing trend towards the developments of TPI as an advanced characterization tool for f i lm coatings in the last decades.Ho and coworkers have demonstrated its capabilitiesto construct 2D maps and 3D models of f i lm coating defects and to determine coating uniformity[12].In this study,TPI was validated by microscopic imaging with respect to the accuracy of measuring coating layer thickness.A new terahertz parameter(terahertz electric f i eld peak strength/ TEFPS)was also introduced by them to determine density of the tablet f i lm coating[6].Correlation of tablet coating thickness as measured by TPI with dissolution behavior was f i rst reported by Spencer and coworkers[16].

Given the increasing amount of studies and use of the technique in industry,it is important to highlight some of the key measurement and signal processing considerations in more detail to avoid artifacts and thus ensure fully quantitative and robust TPI measurements.Brock and coworkers[48] has provided an insight into some critical factors when working with TPI(Table 2).

4.2.Near infrared imaging

Near infrared imaging technology is different from other spectral technology,as it can provide thousands of spectra but not just a single spectrum[1].According to the literatures,the application of this technology in pharmaceutics includes determination of mixing homogeneity of the powder[49]and mixing uniformity of the end products[50],identi fi cation of tablet blister packaging[51],extraction information on the mixture of tablets and preliminary tablets[52].Recently,it is also used to determine tablet content uniformity[53]and examine internal structure of the time-released granules[54]. However,there has been a few reports about its application on fi lm coating[1].Lene Maurer and coworkers employed the near infrared imaging and TPI technology to analyze the fi lm coatingprocess,andcomparedthesetwomethods, concluding that they could provide similar information on the distribution ofcoatingthickness,whileTPIis moresuitablefor analysis of thick coating layer,and near infrared imaging has higher spatial resolution,thus enabling analysis of coating thickness under the TPI detection limit.

4.3.Magnetic resonance imaging(MRI)

The initial analysis of the performance of f i lm coating is usually based on evaluation of casting f i lm,such as elastic strength,wettability and dissolution behavior of the f i lm in the standard release medium[55],etc.Up till now,there have been plenty of novel imaging techniques used for the evaluation of enteric coating system,such as acoustic microscopy, diffusive infrared microscopy,optical coherence tomography [56],etc.Theapplicationofthesetechniquesismainly focused on the analysis of thickness and continuity of the enteric coating[17],the disadvantage of which is that the comprehensive understanding of the coating process shall be carried out on a large amount of samples even at the beginning of the coating progress,and also is time and material consuming. Dorozynski P and coworkers[17]has adopted MRI technology as a novel method for rapid screening of the properties of these enteric coating compositions.Preparation of coated tablets in a f l uidized bed is not essential by this method.The enteric coating model tablets were put in a specif i cally designed testing pool for component analysis.And thefeasibility of this method was conf i rmed in comparison with mini tablet dissolution results,thereby MRI technology can be used for the early screening of f i lm coating formulations.The operationsregardingthistechnologyaresimple,thus reducing the time required to screen coating formulations.

5.Microscopic techniques

Since the sensor sensitivity of PAT may be compromised or blurred with some“dirty”environment,they are not adaptable to all coatingprocesses[5].Somemicroscopic techniques, including confocal laser scanning microscope(CLSM),atomic force microscope(AFM),scanning electron microscope(SEM), etc.can be implemented off-line to extract useful information on coating process.Due to the destructive nature of these microscopic techniques except CLSM,they are not suitable for in-line monitoring of the coating process.However,SEM can be used as a validated method for TPI to determine coating thickness and coating surface,thus providing information on coating variability[11].CLSM was determined to be a fast and effective analysis tool to quantify the coating thickness and distribution,and predict the coating functionality[32].Besides,the CLSM data can be used to characterize the coating qualityand thecoatingthicknessto 1-1.5 μm[57].Moreover,it can be used in a particular case where an autof l uorescent agent is incorporated in the coating layer[4].

6.Film coating analysis

There have been various analytical tools to be implemented for the in-process monitoring of coating in the last decade. And their applications are generally aimed at:(1)measuring coating thickness and coating density,(2)determining process end point,(3)analyzing coating variability/uniformity,(4) plotting coating structure/morphology.

In measuring coating thickness,NIR and Raman spectroscopy are indirect measurement tools and likely to be more effective techniques to be employed in the case of immediate release coatings,where the coating f i lm is thin,while they are sometimes restricted by their need for chemometric models and biased detection for the surface of the coating[50].However,TPI,as a direct measurement tool,is only suitable for the analysis of tablet coating with a minimal coating thickness of 30-40μm[58]dueto lowlateralresolutionlimitof150-200 μm which makes small samples with a high curvature more challenging because of diffuse scattering effects[59].Therefore technological advances for automated analysis of e.g. standard size pellets are desirable,but coating thickness of a single pellet is not of such importance when pellets are compressed into tablets or f i lled in capsules to produce multiunit dosages forms.Unlike the spectroscopic techniques,TPI has the capability to resolve multiple coating layers with a single-point measurement and may not require the set-up and maintenance of robust multivariate analysis models for data interpretation[19,60].Besides,TPI can be used to directly measure coating density based on the density differences between the two tablets surfaces and the centre band due to distinct differences of the peak orientation in the terahertz waveform[61].Generally,a coating/core minimum indicates a higher n(refractive index)of the coating material than of the core and conversely,a maximum indicates a lower n of the coating material compared to the core[59].Some destructive techniques,such as LIBS and SEM,can be introduced as reference or validation methods for the estimation of coating thickness.While in MRI the signals are only acquired during dissolution and thus information on the coating quality can only be obtained indirectly[62].

The determination of coating end point of solid dosage forms in an industrial process should be possible with these spectroscopic methods,especially NIR and Raman spectroscopy,which will be implemented in greater extent[19].It can be performed as a result of predicting coating thickness.

For the determination of coating variability/uniformity, both NIR and Raman spectroscopy are ideal tools due to highspeed analysis and chemical selectivity[3].LIBS is also introduced to rapidly and inexpensively investigate inter/intratablet coating variability by assigning an average coating score based on the obtained data despite its destruction to the measured samples[13].Since the terahertz maps acquired by TPI consist of over one thousand pixels providing detailed information on the coating thickness distribution,coating uniformity is concomitantly determined[12].SEM also provides the possibility to detect intra-tablet or intra-pellet variation in coating thickness after measured samples cutting into halves[19].

In mapping of coated products,TPI holds superiorities over those spectroscopic techniques,as any number of locations in the tablet can be probed[6],and even interfaces located up to 2 mm below the tablet surface of coated tablets can be detected due to deep penetration[58].Besides,a threedimensional map of the coated tablet is achievable as a function of the obtained three dimensional data set,and thus coating defects like craters,scratches,surface roughness and drilled holes(in the case of a push-pull osmotic system)could be detected[19].

7.Conclusions

Film coating which has emerged as early as 1950s,represents animportantunitoperationforproducingsoliddosagedorms, while the implementation of“PAT”for monitoring of this pharmaceutical coating process is still in the experimental stage.The“PAT”guidance was f i rst put forward by the FDA, with the ultimate goal to eff i ciently produce products of high quality.The quality of the f i nal products can be affected by a myriad of processing parameters in the coating process,such as temperature of the inlet and outlet air,pressure of the inlet and outlet air,f l ow rate,spraying rate,etc.These parameters are diff i cult to maintain at a particular level in the actual operation process,which is likely to inf l ict coating variability between inter-/intra-tablets.While the traditional method used to monitor the coating process has many shortcomings, so it is necessary to develop some novel technology for rapid monitoring of the coating process and improvement in the production eff i ciency,thus creating better economic benef i ts.

The application of PAT on f i lm coating was mainly focused on measurement of the amount of coating and coatingthickness,determination of the coating endpoint and coating uniformity,mapping of the coated products,etc.Whereas, these techniques are not suitable for all the coating processes, as the sensitivity of the sensor may be blurred with dirty coating environment and product attributes,resulting in failure to obtain valuable data information.Although it is believed that the implementation of PAT is a promising approach to in-process monitor f i lm coating,more in-depth researches are required for the transition of these technologies from laboratory scale to industrial scale.

Acknowledgements

The work was supported by National Natural Science Foundation of China(81202476)and Medical Research Foundation of Guangdong Province(B2012079).

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*Corresponding author.College of Pharmacy,Sun Yat-Sen University,No.132,Waihuan East Road,Guangzhou Higher Education Mega Center,Guangzhou 510006,China.Tel.:+86 2039943427;fax:+86 2039943115.

E-mail address:pxin_1385@163.com(X.Pan).

Peer review under responsibility of Shenyang Pharmaceutical University.

http://dx.doi.org/10.1016/j.ajps.2014.10.002

1818-0876/©2015 Shenyang Pharmaceutical University.Production and hosting by Elsevier B.V.This is an open access article under the CC BY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/3.0/).

Process analytical technologies (PAT)

Spectroscopic techniques

Imaging techniques