Application of a Fluorescence Sensor for Miniscale On-line Monitoring of Powder Mixing Kinetics

Application of a Fluorescence Sensor for Miniscale On-line Monitoring of Powder Mixing Kinetics CHEE-KONG LAI, CHARLES C. COONEY Department of Chemical Engineering, Building 56-454, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139

Received 20 October 2002; revised 12 April 2003; accepted 25 April 2003

ABSTRACT: A portable system using light-induced fluorescence technology (LIF) was development as an analytical tool for on-line monitoring of various manufacturing process applications. The LIF system was verified in several laboratory scale process applications specifically in noninvasive real-time observations of blend kinetics in tumbler blenders. This technology, through careful selection of filters for specific formulations, can provide clean and unadulterated raw data that shows the actual blend characteristic behavior of powder mixtures such as homogeneity end point and blend stability. Consistent blend homogeneity end point was demonstrated for all runs with LIF where data were verified by thief sampling and UV spectrophotometric assays. A correlation between LIF signal and drug powder concentration was established with limits of detection below 0.02% w/w for the API, Triamterene. ß 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:60–70, 2004

Keywords: light-induced fluorescence; on-line; noninvasive; blend homogeneity; blend stability; pharmaceuticals; powders

INTRODUCTION The current state of art in sampling technology from a static powder bed utilizes a sampling thief. Unfortunately, it has been recognized1–3 that a thief does not always provide a representative powder sample. Sampling errors are sensitive to thief design,4,5 sampling technique,2,6–11 and physical and chemical properties of the formulations.12–15 Because of this, the Product Quality Research Institute recently formed a Blend Uniformity Working Group and recommended new approaches that can be used to satisfy the cGMP requirement for in-process testing to demonstrate adequacy of mix, as well as USP compendia release requirements for the content uniformity of finished dosage forms.16 In addition, the FDA also recently introduced a new initiative to encourage Correspondence to: Chee-Kong Lai (Telephone: 978-3020096; Fax: 815-333-1946); E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 93, 60–70 (2004) ß 2004 Wiley-Liss, Inc. and the American Pharmacists Association

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the pharmaceutical industry to apply modern process analytical technology (PAT) to pharmaceutical production and quality control.17 The objective of this initiative is to reduce the time to market; this has the expected benefit to reduce cost of goods. Furthermore, these technologies will improve product quality, increase manufacturing efficiencies, improve quality assurance processes and also reduce regulatory burden on the FDA. Unfortunately, no one single technology is universal to all compounds, and practitioners will require the knowledge to select the best instrumental technology for each application. We have previously reported18 the development of a light-induced fluorescence (LIF) sensor specifically for noninvasive and on-line monitoring of blend homogeneity of dry powders. The local concentration of the fluorescent active pharmaceutical ingredient (API) can be tracked selectively by monitoring the signal of the corresponding emission wavelength in response to light excitation. An examination of many of the leading pharmaceutical products showed that their ‘‘drug-like’’

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structures composed mainly of substituted aromatics and heterocyclics, which are candidates that may have some degree of fluorescence property. A recent review article listed the top 10 leading pharmaceutical product sales in the world for the year 2000 (http://www.contractpharma. com/JulyAug021.htm). Eight of these 10 products are assessed to have some form of fluorescence properties. Another review of the chemical structures of the Top 200 Pharmaceuticals from the RX Web site (http://www.rxlist.com/top200.htm) also showed that greater than 60% are potential candidates with fluorescence property. These surveys provided further encouragements that LIF can be a potentially useful technology to explore applications in pharmaceutical manufacturing processes. In this article, we describe the use of a battery operated and portable LIF sensor using a flashlamp as the light source with wireless transmission of data. We present results of noninvasive miniscale studies on monitoring blend kinetics of powder mixtures in different tumbler-type blenders. The results in acquiring these data noninvasively throughout the period of the mixing process may be compared to thief sampling with the exclusion of sampling errors and off-line analysis. From these dynamic measurements, the real-time blend kinetics can provide quantitative information on the drug concentrations of the entire bulk, the blendability of the formulations and the stability of the formulations towards segregation on discharge. Allen19 has suggested that the dynamic powder sampling method is more superior to static sampling20 based on his rules that a powder should be sampled in motion and that the whole stream of powder should be taken for many short increments of time in preference to part of the stream being taken for the whole of the time. The use of miniscale at 10 to 20 g total material is useful for early phase formulation development when only small amounts of the active ingredient are available. It also provides ease in handling and the opportunity for examining the scale-up characteristics of the formulation.

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Figure 1. Simplified Diagram of the Portable LIF Sensor.

source, a photomultiplier tube detector, bandwidth filters (from Omega Optical, Inc.) and optics. The wavelength ranges used are indicated in the respective cases mentioned. The power unit contained a 4-h rechargeable battery (Plainview Batteries, 36 V, 600 mA), a position synchronizing trigger (mercury switch or infrared gate) and a radio frequency transmitter (WIT2400, 2.4 GHz spread spectrum) for remote transmission of data. The unit functioned well in an ambient light environment without light shielding except when operating at high detector sensitivity. The focusing distance and beam size can be altered by selection of different lenses. Current beam size used is 5 mm at a focus distance of 30 mm from the powder interface. Typically, between 10 to 20 g of total materials are used in studies with the miniblending system. The sensor is placed in a stationary position with the blender rotating around it. Synchronized data acquisition at the quartz (or sapphire) window is controlled by an on/off infrared gate as shown in Figure 2. For larger scale studies, the instrument is physically attached to a blender window. Synchronized data acquisition is then controlled by a mercury position switch where data in the form of radio waves are transmitted to a nearby receiver attached to a computer. Real-time blend profiles are displayed using software from LabView that shows the consistency in end-point determination, the correlation of signal to concentration of drug and the sensitivity to changes to the method of drug addition to the blender.

The LIF Sensor The portable LIF sensor consists of two parts, the Flashlamp Unit and the Power Unit, each with dimensions 30.48
15.24
10.16 cm. Figure 1 shows the unit, which contained a flashlamp light

Model Compounds and Solid State Fluorescence Spectral Properties Triamterene (2,4,7-triamino-6-phenylpterine) is a highly fluorescent active pharmaceutical JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 1, JANUARY 2004

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tions greater than 1% w/w drug. The optimal excitation wavelength at 400 nm is used for drug concentration less than 1% w/w drug. Optimal parameter settings for other drug substances are determined based on signal-to-background ratios. Penetration Depth of LIF in Powders

Figure 2. LIF Sensor with mini-blender and trigger mechanism.

ingredient (API) obtained as a gift from GlaxoSmith-Kline. This is a cohesive powder of particle size between 10–30 mm with a bulk density of 0.3 g/cc. The compound is chosen for its strong fluorescence upon excitation at wavelengths from 350 to 500 nm. The primary excipient is anhydrous lactose for direct compaction (#5X59009, lot 016120105, Sheffield Products, New York) of mean particle size 100 mm and bulk density of 0.6 g/cc. To demonstrate the versatility of this LIF technology, other APIs such as Amoxicillin (WHA 35200), RPR118749 with different fluorescent properties and Orlistat with nonfluorescent property are also used and their blend characteristics described in their respective sections. Solid-state fluorescence spectra of the drug powder is obtained using front face optics at its tap density in a FluoroMax-2 Fluorimeter (ISA Jobin Yvon-Spex) equipped with modified CzernyTurner spectrometers and DataMax software. Study Design and LIF Unit Verification Most of the following work was done with a formulation consisted of Triamterene as the active pharmaceutical ingredient (API) and anhydrous lactose, as the bulk filler with a 0.1% Carbosil as a flow enhancer. Because Triamterene is an extremely fluorescent compound, the weaker response generated by the longer excitation wavelength of 480 nm is selected for use with drug concentraJOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 1, JANUARY 2004

A 10-mm diameter and 3 mm-thick sample wafer containing 200 mg of a 5% Triamterene in anhydrous lactose was compressed at 2000 psi using a carver hydraulic press. This wafer was placed below the LIF sensor, 30 mm from the lens. The initial LIF response of this drug surface was recorded using parameters as determined in early sections. Another powder chamber of the same dimension was created on top of the Triamterene wafer using slices of cardboard 0.25 mm thick. Layers of 0.25 mm anhydrous lactose powder was placed on top of the drug containing wafer followed by measurement of the resultant LIF response at each layer. Monitoring of the Mixing Process of Different Triamterene Concentration Formulations Different formulation batches containing 4.5% (0.332 g Triamterene, 0.007 g Carbosil, 7.004 g lactose), 3.1%, (0.225 g Triamterene, 0.007 g Carbosil, 7.006 g lactose), and 1.6% (0.116 g Triamterene, 0.007 g Carbosil, 7.004 g lactose), Triamterene-lactose were prepared. Triamterene was added last at a position away from the monitoring window. Blending was performed in a tube blender (20 mm diameter, 100 mm long) and monitored at the bottom window. A filter set (XF22, Omega Optical, Inc.) was used with excitation at 480 nm (band width 22 nm), emission at 520 nm (bandwidth 30 nm) and instrument sensitivity at 400 mV. A single datum point was acquired upon synchronized activation at a constant position for each rotation. Very low concentration blending formulations at 0.57% (0.0400 g Triamterene, 0.0108 g Carbosil, 6.9625 g lactose), 0.15% (0.0104 g Triamterene, 0.0067 g Carbosil, 7.0144 g lactose) and 0.02%(0.0017 g Triamterene, 0.007 g Carbosil, 7.006 g lactose) were also prepared. A different filter set (XF136, Omega Optical, Inc.) was used with excitation at 365 nm (bandwidth 50 nm) and emission at 450 nm (bandwidth 58 nm). This filter set made use of the optimum fluorescence response from Triamterene to enable monitoring of very low drug concentrations. In these cases, Triamterene

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was added at the bottom of the window (near the monitoring source) so that we could track the change in signals even at the low drug powder concentration. The blend process was monitored at 290 mV to meet sensitivity requirements. Monitoring End-Point Consistency of Two Different Blender Sizes Minibin blenders, made from polyethylene terephthalate polymer were used. An opening in the blender functioned as the loading and discharge port where the enclosure is a cap with a window made from 1/4 inch polished quartz. Two bin blenders of similar shape ratio at 130 mL (Blender A) and 400 mL (Blender B) in volume were used. Noninvasive monitoring of blending profile was conducted through the quartz window cap at the discharge spout. Monitoring of all dynamic blend profiles in real-time was conducted through a single position at the quartz window of the cap enclosure similar to the setup shown in Figure 2. A constant 50% working volumes was used for each blender and a constant formulation comprised of 2.5% Triamterene in anhydrous lactose and 0.1% Carbosil. The composition of blender A comprised of 0.8 g Triamterene, 30 g anhydrous lactose, 0.3 g Carbosil, and that for blender B comprised of 3.0 g Triamterene, 120 g anhydrous lactose, and 1.2 g Carbosil. Comparison of On-line Monitoring, Static MultiPosition Monitoring and the Use of an Optical Thief Sampling Probe Amoxicillin (WHA 35200, bulk density 1.7 g/cc, particle size 2–10 mm) was used in this study where the blend process was conducted in a 135 mL glass tube-type tumbler with dimensions of 11.43 cm (length) by 6.35 cm (inner diameter). Formulations were derived with lactose monohydrate (DCL-11, Pharmatose from DMV International, bulk density 0.6 g/cc, particle size 100 mm) as the bulk diluent with 0.1% Carbosil. Concentrations of Amoxicillin from 0, 1, 3, 5, 10, 15, and 20% w/w were prepared. The blend kinetic profiles were monitored in real time from a distance of 30 mm and at a position 1/3 from the bottom of the vessel as shown in Figure 3. A filter set (XF13, Omega Optical, Inc.) was used with excitation at 405 nm (bandwidth 40 nm) and broad emission band from 460–640 nm. The process was stopped when homogeneity was indicated by a steady LIF signal. At end point, the resultant

Figure 3. Comparison of On-line Monitoring, Static Multi-Position Monitoring and thiefing using an Optical Probe.

static powder mixture was scanned at eight different positions of the vessel as shown in Figure 3. A custom optic fiber reflectance probe (Ocean Optics, Inc.) attached to a miniature USB2000 Fluorescence Spectrometer (Ocean Optics, Inc.) was used as a thief to analyze the powder content inside the vessel at the proximity of surface position scanned. The same filtered flashlamp light source from the LIF instrument was used. The data were acquired for a period of 1000 ms.

Monitoring of Blend Profiles of a Nonfluorescence API Using Excipient Background Signals An approach to investigate the strategy for monitoring blend homogeneity of a nonfluorescent API in a formulation is to utilize the background fluorescence properties of its excipients. Orlistat is an active pharmaceutical ingredient that has a molecular structure that does not fluoresce. All excipients and drug used in a formulation were evaluated for their LIF responses using the filter set, XF13 (Ex ¼ 405 nm, bandwidth ¼ 40 nm; Em ¼ 460–630 nm). All the excipients were mixed together in a proprietary ratio required for the formulation to form the placebo. The ratio of signal response of the placebo to that of Orlistat was determined at the detector sensitivity of 363 mV to provide confidence in using LIF to monitor blend homogeneity. To further demonstrate feasibility, several different concentrations of the Orlistat formulations ranging from 20 to 60% w/w API were prepared. The mixing kinetic profiles were run in the minitube blender and monitored in real-time. The resultant blending profile were determined and homogeneity end point using LIF was verified by sampling and UV spectrometry. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 1, JANUARY 2004

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Comparison of Blend Profiles of an API in Two Different Excipients An API (RPR118749) of particle size 190 nm and bulk density of 0.3 g/cc was used. A 0.5% (w/w) API formulation was made up with either spray dried lactose monohydrate (Pharmatose DCL-11, DMV International, particle size 100 mm and bulk density 0.60 g/cc) or microcrystalline cellulose (PH102, FMC, particle size 90 mm and bulk density 0.30 g/cc). A V-blender of about 50 mL total volumes was used. A 12-g portion of the 2% API was mixed at a rate of 10 rpm. A filter set (XF01, Omega Optical, Inc.) with excitation at 254 nm (bandwidth 25 nm) and emission at 330 nm (bandwidth 60 nm) were used at 464 mV detector sensitivity. These filters were chosen for good selection of the drug over the various excipients (see Fig. 4). The respective excipients in each formulation were sieved with a 600-mm screen to remove clumps, weighed out, and placed into the Vblender. The volume of powder used was always maintained at 50% working volume of the blender to ensure good mixing. LIF data were acquired through the quartz window at the bottom of the V-blender (see Fig. 2). Data acquisition was synchronized such that only one datum point was acquired each time the blender moved into that location during each rotation. The powder mixtures were mixed for 100 rotations. Data from the last 40 rotations were analyzed and the standard

deviations calculated after a homogeneous steady state had been established (at 60 rotations). The resultant standard deviation recorded represents the dynamic stability of the powder after end point was achieved. The powders then were discharged into a segmented column shown in Figure 5. Seven segments were collected for each run. The contents from each segment were collected, weighed, and dissolved in a known volume of methanol. Concentrations of the API were determined with UV spectrometry from a concentration calibration curve (data not shown). The standard deviation in concentration from all the segments of the respective batch of formulation was calculated.

RESULTS Fluorescence Spectra of Triamterene Powders A solid phase fluorescence spectrum of Triamterene (Fig. 6) was obtained at the excitation wavelength of 400 nm; the maximum emission response was at 460 nm. At a second excitation wavelength of 480 nm, two emission maxima were observed at 528 and 560 nm. The fluorescence response when excited at 400 nm was 16-fold stronger than that at 480 nm. This provided a choice in selection of the excitation wavelength depending on the concentration level of the active ingredient. Penetration Depth of LIF in Powders

Figure 4. Response of filter XF01 to RPR118749 and the excipients used. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 1, JANUARY 2004

Layers of nonfluorescence lactose powder were built up in 0.25-mm increments on top of a fluorescent surface. As the powder thickness increased, an exponential decrease in signal was observed as shown in Figure 7. The signal decrease leveled off at about 1.5 mm, at which point a slower rate of decrease took place. Even at the depth of 7.5 mm, about 4% of scattered fluorescence signals could be detected above background, probably due to random photon migration through the particles. These observations are typical expected outcome for most reflectance optical techniques. The eventual penetration characteristics are dependent on the wavelength used, the particle size, and the packing density of the powder bed. In most cases, practical penetration of the light source using this LIF technology would not be more than 1 mm in depth. For most considerations in general, fluorescent data would mostly be contributed from the powder surfaces.

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Figure 5. Discharge of blender materials into a segmented column for analysis of segregation.

Monitoring of the Mixing Process of Different API Concentration Formulations Figure 8 showed the real-time blend kinetic profiles of mixing monitored for the three different concentrations of Triamterene in anhydrous lactose. Early phase convective mixing can be observed in this tube-type blender from the beginning up to about 20 rotations. From observation of the blend profile, a final homogenous steady state was not reached in the three examples until after about 80 rotations in this type of tube blender. A plot of the filtered standard deviation of the blend profile data using five consecutive data points (see Fig. 9) provided a

more distinctive description of the three stages of mixing, the convective, shear, and diffusive mixing.21,22 For API concentrations greater than 5% w/w, it is often difficult (and unnecessary) to distinguish diffusive mixing from homogeneous end point. For measuring very low concentration drugs, the API was placed at the window to maximize the initial stage of the signals. The blend profiles for very low concentration blending formulations (0.57, 0.15, and 0.02%) are shown in Figure 10. The blend profiles for these low concentrations were well defined. A signal level difference could be established between the placebo and the lower concentration of 0.02% w/w API in the formulation. A linear correlation curve was established from the average signals at homogeneity to fit an equation with R2 of 0.993. Monitoring End Point Consistency of Two Different Blender Sizes

Figure 6. Solid phase fluorescence spectra of Triamterene. Different levels of emission response can be achieved through excitation at different wavelengths.

Two minibin blenders with comparable shape but different sizes were used in a setup described in the experimental section for a 2.5% Triamterenelactose formulation. The blend profiles and end points were monitored in real-time at a single window. The results (see Fig. 11) showed that the blend profiles were similar and consistent with each other. These data clearly defined the early phase convective mixing from the beginning to the first 10 blend rotations followed by predominantly JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 1, JANUARY 2004

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Figure 9. Changes in filtered standard deviation (n ¼ 5) as an indicator for homogeneity end point. Figure 7. Response of LIF through loosely packed powders to simulate penetration of LIF into the bulk powder material during mixing and monitoring at the window.

shear mixing from the 10th to the 25th rotations. The diffusive mixing state and homogeneity end point were less well defined, and generally depended on the definition of the manufacturers release criteria. For this example, the end point was determined when the RSD was 1% of the mean signal. The differentiation between diffusive mixing and homogeneity end point would be more critical for direct blending of a very low dose API (e.g., 0.1%).

Figure 8. Typical blend profiles of various concentrations of Triamterene in lactose in a tube tumbler-type blender. Excitation ¼ 485 nm (bandwidth 22 nm); Emission ¼ 530 nm (bandwidth 30 nm); Sensitivity ¼ 400 mV. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 1, JANUARY 2004

Comparison of On-line Monitoring, Static Multiposition Monitoring and the Use of an Optical Probe The study described earlier was performed to verify online monitoring with thief sampling of a powder bed. A series of formulations containing various concentrations of an API were prepared. The relative standard deviation of the on-line LIF signals, after homogeneity, was determined at a fixed blender surface position. After blending was stopped, the blender surface was then monitored again at multiple positions. An optical thief (LIF reflectance probe) was also used to sample inside the powder bed at proximity to the surface from which the powder composition was scanned noninvasively (see Fig. 3). These data were compiled and shown in Figure 12. The results showed no significant difference between dynamic and static measurements. The RSD was relatively low and similar between these two measurement techniques (see Table 1). Measurement of the powder bed concentration at the interior with an optical thief incurred a much larger RSD. This difference might be the result of different measurement technique and instrument configuration. Even though the light source was the same, the detector was different (a CCD spectrometer versus PMT) and the volume of sampling was significantly smaller (0.8 mm3 probe versus 15 mm3 lens) due to the use of optic fibers. However, the qualitative behavior was similar with respect to data obtained from LIF surface scan. Data obtained from the various thieved locations for each respective API concentration samples had significantly higher deviations than that for the LIF scans. There are two possible explanations for these observations. First, probing could

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Figure 10. A. Blend profiles of low concentration Triamterene formulations using a high sensitivity light filter system. Excitation ¼ 365 nm (bandwidth 50 nm); Emission ¼ 450 nm (bandwidth 58 nm); Sensitivity ¼ 290 mV. B. Linear correlation between signal and % API at low concentrations.

disrupt powder beds causing local segregation or powder packing differences and second, the smaller sampling volume (0.8 mm3 versus 15 mm3) could impart higher resolution, and hence, were able to differentiate very small variations in powder composition. We believe that bed disruption and changes in packing density are the likely causes of sampling errors as exemplified by the large RSD recorded for the placebo with 0% API.

Monitoring of Blend Profiles of a Nonfluorescence API Using Excipient Background Signals

Figure 11. Comparison of the blending profiles of a 2.5% Triamterene/lactose formulation in 2 different size bin-blenders. Excitation ¼ 485 nm (bandwidth 22 nm); Emission ¼ 530 nm (bandwidth 30 nm); Sensitivity ¼ 365 mV.

Figure 12. Comparison of on-line monitoring, static multi-position monitoring and an optical thief probe. Excitation ¼ 405 nm (bandwidth 40 nm); Broadband Emission ¼ 460 nm–600 nm); Sensitivity ¼ 330 mV; Reflectance probe, 1000 ms integration period @500 nm.

Orlistat showed a very low background signal at a ratio of 1:10 when compared to the placebo formulation (see Fig. 13) from these fluorescence evaluations using an excitation filter at 405 nm (bandwidth 40 nm) and an broad emission filter from 460 to 630 nm.

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Table 1. RSD from the Different Measurement Techniques API, % w/w Dynamic mixing Static multiscan Reflectance probe

0

1

3

5

10

15

20

1.03 1.75 26.67

0.92 2.78 13.45

1.20 2.34 8.92

1.07 2.09 8.31

0.69 1.14 7.37

0.46 1.39 7.82

1.76 1.62 2.73

These large differences in responses provided us with sufficient confidence in using LIF to monitor blend homogeneity. The various blend profiles from the Orlistat formulations ranging from 20 to 60% were shown in Figure 14. Excellent mixing profiles were recorded. The equilibrium end points corresponded well to that of a calibration curve where the responses to LIF were measured and found to be linearly and inversely proportional to the drug concentration. Comparison of Blend Profiles of an API in Two Different Excipients The profiles for the mixing kinetics of the two formulations describe earlier were shown in Figure 15. Data for all formulations were analyzed from 50 to 80 rotations, irrespective of whether equilibrium had been established. When the LIF blend profiles were examined at homogeneity steady state, differences in signal variations between mixtures formulated with lactose (DCL-11) or microcrystalline cellulose (Avicel PH102) were observed. The API formulated in PH102 had a signal relative standard deviation (RSD from rotations 50–80) of 2.96%, while the formulation with lactose showed an RSD of 11.24% for the same period of rotations. Because this LIF technique measures a constant volume of powder at the window during each rotation, a low RSD in the signal profile after homogeneity had been established indicated a powder formulation that do not change in composition from one

Figure 13. Response of excipients and Orlistat to LIF using the filter set XF13 at sensitivity of 365 mV. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 1, JANUARY 2004

rotation to the next during dynamic monitoring. This is an indication of a stable formulation that does not show segregation of the API from its excipients. On the contrary, when the RSD is large, the indication is that the dynamic measurement of the composition of the powder at the window seemed to change from one rotation to the next. This is an indication of an unstable and incompatible formulation. To verify these observations, the final blend at end point was totally discharged into a segmented column. The dimension of each segment measure 25 mm in diameter in sections of 10 mm thickness, each of which would typically hold about a three dose size of powder. These individual segments were dissolved in methanol and analyzed by UV spectrometry at 310 nm for API content. The RSD of the UV analysis of the respective segments showed better homogeneity for the formulation in PH102, while segregation and destabilization was suggested for the formulation in lactose DCL-11. The RSD for the UV analysis data were generally higher. This may suggest a higher degree of uncertainty for human error during the preparation of the assay or that the action of discharging induced additional segregation of the powder. Both UV analyses of the segments verified the on-line analysis of the LIF blend profiles (see

Figure 14. [A] Blend profiles and [B] Correlation of LIF signals to various formulations containing different % Orlistat w/w. Excitation ¼ 405 nm (bandwidth 40 nm) and an broad emission filter from 460 to 630 nm.

FLUORESCENCE SENSOR FOR ON-LINE MONITORING OF POWDER MIXING KINETICS

Figure 15. Mixing profiles of a 2% API formulated with 2 different excipient with different physical properties. Excitation ¼ 254 nm (bandwidth 25 nm); Emission ¼ 330 nm (bandwidth 60 nm); Sensitivity ¼ 464 mV.

Fig. 16). The particle size of both excipients used in this formulation was comparable (100 and 90 mm, respectively) but their bulk density seemed to differ (0.60 and 0.30 g/cc, respectively). The API (RPR118749) had a particle size 190 nm and bulk density of 0.3 g/cc. In this limited study, the excipient with a similar bulk density with that of the API seemed to produce a more stable mixing profile. It also suggested that formulation stability may be determined during real time monitoring of the process using LIF.

DISCUSSIONS A portable LIF device capable of real-time, noninvasive monitoring of powder blending process

Figure 16. Comparing RSD of LIF signals from dynamic measurements and UV analysis of the total segments.

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had been successfully demonstrated at laboratory scale. The ability to use LIF at multiple process points in real-time made it a potential tool for implementation onto the Process Analytical Technology platform. The LIF instrument uses a flashlamp that provides 125 milli-Joules of energy. This amount of energy is low, but sufficient to induce detectable fluorescence signals on many pharmaceutical compounds using a highly sensitive solid phase photomultiplier tube. The useful excitation range for most pharmaceuticals is between 200 and 400 nm. The use of a flashlamp with a wide wavelength range is useful for the development stages of a process, as it can provide the range of excitation wavelengths that is necessary for the variety of compounds in the pharmaceutical industry. The classical mechanisms of powder mixing in tumble mixers have been described as convective, shear, and diffusive.23,24 The mixing profile and changes in the dominant mechanism from convective, shear, to diffusive as the period associated with heterogeneity within the blend decreases can be described from real-time LIF monitoring of the process, as shown from results provided. This technology, through the selection of specific filters for specific formulations, can provide clean unadulterated raw data that shows the actual characteristic behavior of the powder. Changes to the physical properties of the composition of the material that affects the blend properties can be observed through real-time monitoring of the blend profile. The technology, however, has two primary limitations that prevent it from being considered as a universal method. The first limitation is the requirement for either the API or some of the excipient to have some low level fluorescence property. This technology can function as long as there is differentiation between signals from one component with the other. The second limitation is that the technology can only be used for dry blend, semisolids, or liquids where there is an efficient changeover of materials at the monitoring window. Substantial blockage of the window with a static amount of wet or cohesive material will reduce the ability of the sensor to provide accurate measurement of the composition changes within the vessel. The results shown have used formulations that have good flowability and do not clog the windows at which LIF data are acquired. In most of these cases studied, the abrasive nature of the powders is sufficient to clean the window from one rotation to the next. The results shown earlier indicated JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 93, NO. 1, JANUARY 2004

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that signal levels from the fluorescent bulk powder mixture can be maintained up to about 0.5 mm of powder coverage. Dusting of window surfaces from these concentrations of API used generally do not contribute to significant changes in the fluorescent signals. Considering the depth of penetration of the excitation source, the technique will not work well with materials that tend to cake heavily at the windows. Window cleaning devices such as mechanical wipers or other automatic lens cleaning devices may be solutions for such formulations. Blockage of the window is generally a sign of a bad formulation that would result in either static charge desegregation or poor flowing material. Hence, use of LIF for continuous real-time monitoring of powder composition for homogeneity during a blend process is not only an improved and consistent noninvasive method to determine blending end point, but the technology can also provide additional information on the mixing mechanism and the compatibility of the formulation itself. These results may lead to other potential applications such as on-line monitoring of tablet production profile, determining powder segregation during discharge or storage and other manufacturing processes that require rapid monitoring of changes in uniformity.

ACKNOWLEDGMENTS The authors acknowledge the financial support from the Consortium for the Advancement of Manufacturing in Pharmaceuticals (CAMP). We thank Peter Hansen and his group at Union Biometrica, Inc. (UBI) for assembling the LIF equipment and Stephen J. Alam (UBI) for suggestions in software development.

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