Abstract:
A fiber optic probe ( 100 ) provides in-vitro measurement for measuring fluid media containing bubbles and particulate matter where disturbances to fluid dynamics must be kept to a minimum. The probe transmits light to, and receives light from, the measured fluid media across a light-path gap ( 119 ) using two, separate fiber support tubes ( 107 A,  107 B) to protect the transmitting and receiving fibers and provide a rigid and resilient structure. Each support tube, containing one or more fibers, is bent ninety degrees in a smooth quarter circle to produce a light path gap that is perpendicular to the longitudinal axis ( 113 ) of the probe. A cross-member ( 125 ) provides precise alignment of the optical axes or the transmitting and receiving fibers. The small-diameter support tubes reduce hydraulic flow disturbances and debris buildup which would occur with conventional probes during tablet dissolution. The transverse light path gap reduces opportunities for debris buildup and bubble entrapment between transmitting and receiving optical surfaces.

Description:
FIELD OF THE INVENTION 
     The present invention relates to fiber optic probes for spectrophotometry. In particular, the present invention relates to a fiber optic probe optimized for absorbance measurement applications in fluid media where bubbles, particulate matter, measurement sensitivity, stray light rejection, and flow dynamics are a concern. The present invention further relates to automated, multi-channel spectrophotometric measurements that employ multiple fiber optic probes coupled to either multiple single-channel spectrometers, multiplexed single-channel spectrometers, or single multi-dimensional “imaging” spectrographs that employ a two-dimensional CCD (charge-coupled-device) array as the detection and measurement element. 
     BACKGROUND OF THE INVENTION 
     Spectrophotometric absorbance measurements are typically performed by measuring the amount of light (I 0 ) that passes through subject media which contains no sample components of interest and then measuring the amount of light (I) that passes through the subject media that does contain the sample component to be measured. The quantity I 0  is referred to as the reference or blank light intensity and the quantity I is referred to as the sample intensity. The concentration of the sample component of interest is proportional to the Absorbance (A), where A=−Log 10 (I/I 0 ). 
     The terms “spectrograph” and “spectrometer” are often used in reference to the same instrument type. However, a spectrograph is a special case of a spectrometer that uses a stationary grating and has no parts (other than a shutter in some cases) that move during the measurement cycle. Light is instantaneously diffracted horizontally across the surface of a multi-element array detector (CCD or photodiode). Some spectrometers use a motorized grating to scan across the spectrum and direct light through an exit slit onto a single-element detector. 
     When fiber optic technology is used, light from a source may be transmitted across a light path gap in the subject media by one or more transmitting fibers, and received by one or more receiving fibers which direct the transmitted light to the detection and measurement device. Probes using this approach are referred to as transmittance probes. In a variation of this basic technique, the transmitting and receiving fibers are side by side and a mirror is used to reflect light back through the subject media onto a receiving fibers. This, in effect, doubles the light path gap. 
     The applications of in situ or remote measurements using fiber optic spectrophotometric probes has increased significantly in step with advances in fiber optic technology, spectrometry and computing hardware, and data collection and processing software. Many commercial systems now support a wide range of in situ spectrophotometric applications which monitor multiple signals from either multiplexed individual spectrometers or single spectrographs employing two-dimensional CCD detector arrays. Only within the last five years have these advances been applied to commercial in situ spectrophotometric monitoring systems targeted to pharmaceutical in vitro dissolution testing. 
     There have been minimal advances in fiber optic probe design that target the specific needs of pharmaceutical dissolution testing where flow dynamics and particulate interference are primary concerns. The maintenance of constant flow dynamics throughout an in vitro dissolution test is a major concern of pharmaceutical laboratories that are required by law to perform dissolution testing before allowing product dosage forms to be sold. The in vitro dissolution testing must be done in accord with standards and procedures defined by the U.S. Food and Drug Administration and the United States Pharmacopoeia. Published studies have shown that large diameter probes alter flow dynamics and cause observed tablet dissolution rates to be abnormally high. 
     Fiber optic probes used in all current commercial in situ dissolution testing systems are based on insertion probe designs commonly employed in industrial environments where the probe must be highly rugged and cylindrical. Typically, the transmitting and receiving fibers are side-by-side (parallel) and in the same enclosure which has a uniform diameter over the submerged portion of the probe. The uniform diameter allows the probe to be readily inserted into a reactor, flowing stream, or other vessel where a seal between the probe and vessel walls is required. Dissolution testing and other forms of laboratory-based testing, where fluid media in a wide-mouthed, unsealed vessel is monitored, have no such requirements for extreme ruggedness or cylindrical configuration. 
     OBJECTS AND SUMMARY OF THE INVENTION 
     Therefore, an object of the present invention is to fully meet the needs of laboratory-based, in vitro pharmaceutical dissolution testing and other types of laboratory testing with similar requirements. 
     Another object of the present invention is to provide a probe for sampling fluids which provides a direct light path between a transmitting optic fiber and a receiving optic fiber without the requirement for additional path-altering optic elements such as mirrors or prisms. 
     Another object of the present invention is to provide a probe for sampling fluids which improves the optic efficiency over earlier designs, allows small-diameter optic fibers and support tubes to be used to reduce flow disturbances in the sample gap area. 
     Yet another object of the present invention is to provide a probe for sampling fluids which reduces or eliminates probe surfaces that can trap air bubbles or accumulate debris in the sample gap. 
     The present invention is a fiber optic probe that includes an open, fine-bodied probe structure and an efficient means of transmitting source light through fluid media to one or more receiving fibers. The probe structure offers minimal resistance or disturbance to fluid flow in the sample area and thus minimizes any affect on solution hydrodynamics or turbulence. The features of one embodiment of the invention are an open structure, very low probe displacement volume and surface area, a light path gap that is perpendicular to the longitudinal axis of the probe in the preferred embodiments, and an efficient means of coupling transmitted light to the receiving fiber that employs no internal optic elements or fiber end modifications. The latter feature also ensures that the invention has excellent stray-light rejection characteristics. Because of its simplicity the probe is economical to manufacture. 
     Elimination of a discrete light reflecting or refracting element such as a mirror or prism increases the efficiency of light throughput for a given fiber size. Thus it becomes possible to employ smaller diameter fibers than would be required when a discrete light reflecting or refracting element is present. This translates to a significant advantage over conventional designs when the present invention is coupled with a multi-channel “imaging” spectrograph based on a two-dimensional CCD array detector. 
     Coupling to the spectrograph is achieved by bringing the distal ends of receiving fibers together into a vertical array bundle that is mounted to the input of a commercially available spectrograph. The spectrograph employs a fixed grating to diffract the light across the wavelength range of interest and additional optic elements to image the multiple light beams onto the surface of a two-dimensional CCD array. Example arrays are composed of 256×256, 512×512, 1024×1024, and other variations on detecting pixel configurations. A CCD spectrometer that could formerly support a maximum of six to eight probes using prisms and 600 μm fibers would now be able to support 12 or 18 “transverse light path” probes of the present invention design using 300 or 200 μm fibers. This translates to a significant advantage in the application of dissolution testing which is done in groups of six to eight vessels. The CCD spectrometer in the previous example would now be able to support up to three dissolution baths or experiments at the same time. 
     The probe of the present invention significantly reduces the cost of equipment required to automatically monitor multiple dissolution tests by elimination of expensive optic elements in the optic probe and increasing the number of channels which one spectrograph can monitor. Multi-channel instruments can monitor more probes of the current design as compared to conventional probes. 
     In use, one or more probes are inserted into the reference fluid media and the reference intensities are measured and recorded. If the concentrations of chemical species are to be measured, then the probes will be inserted into solutions containing a known concentration of reference standard chemical. The reference standard absorbance values will be measured and response factors calculated for each probe. These factors will be used to convert sample absorbance values into concentration values. The probes are then rinsed and inserted into the sample fluid media and monitoring of the sample intensities is performed according to the requirements of the particular application. 
     In the example application of pharmaceutical dissolution testing, the probes are placed into standard, wide-mouthed dissolution vessels from above the fluid media surface. Typically they are held in place by a suitable clamp or holder for the duration of the test, or they may be periodically raised above the sampling point by an automated mechanism for periods of time when measurements are not being made. The latter action may be needed to reduce effects on solution hydrodynamics produced by conventional insertion probes. The clamp that holds the probe structure must be adjustable to allow for different sampling heights that correspond to different solution volumes that may be employed during the dissolution test. The USP standard sampling point is half way between the top of the stirring element (paddle or basket) and the top of the test solution. Thus the distance from the light path gap to the vessel cover will vary depending on the solution volume. The clamp must allow the operator to properly configure the probe “sampling height” prior to starting the test. 
     During the course of sample measurements, bubbles may be produced as a result of liquid media de-aeration. In some applications, as in pharmaceutical dissolution testing of dissolving tablets, particulate matter will also be present during the entire measurement period. The open structure and transverse light path of the present invention helps ensure that particulate matter and bubbles will not be trapped in the light path gap and produce erroneous absorbance measurements. The low displacement volume and surface area of the present design allows the probes to remain in the vessels for the duration of the test and obviates the need for an additional automated mechanism to raise the probes above the sampling point. 
     Together the different embodiments of the present invention form a family of fiber optic probe designs that can accommodate a wide range of sensitivity or light path length requirements for monitoring a variety of pharmaceutical dosage forms during dissolution tests. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     These and other features, aspects and advantages of the present invention will become better understood with regard to the following description, appended claims and accompanying drawings where: 
     FIG. 1 is a front elevation drawing of a preferred embodiment of the present probe design showing the bent tubing structures which contains the transmitting and receiving fibers and the structural members which tie the two bent structures together and maintain fiber alignment; 
     FIG. 2 is a detailed front cross section of the light path gap area of the probe of FIG. 1 showing the transmitting and receiving fiber ends and a structural cross-member used to maintain alignment at the light path gap; 
     FIG. 3 is a front elevation drawing of an optic probe assembly comprising the optic probe of FIG. 1, and an upper support assembly for supporting the probe in a sample vessel; 
     FIG. 4 is a side elevation drawing of the probe assembly of FIG. 3; 
     FIG. 5 is a schematic drawing of a multi-channel, fiber optic-based UV spectrometer system comprising ten optic probes of the present invention connected to a single spectrograph via multiple transmitting and receiving optic fibers. 
     FIG. 6A is a front view of an alternative embodiment of the present invention showing an elongated tube portion and two lower curved tube portions having symmetric or mirror-image compound-curved tube portions providing a direct path light gap; 
     FIG. 6B is a front view of an alternative embodiment of that shown in FIG. 1 wherein the elongated body portion spreads or fans outward towards the proximal end; 
     FIG. 6C is a front view of an alternative embodiment of the present invention showing a “U” shaped probe and a sample gap having a longitudinal axis parallel with the longitudinal axis of the probe; and 
     FIG. 6D is a front view of an alternative embodiment of the present invention having an integral body assembly. 
    
    
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The following is a description of the preferred embodiments of a fiber optic probe for measuring fluid media and a method for automated, multi-channel spectrophotometric measurements utilizing the probe. 
     FIG. 1 shows a optic fiber probe  100  according to a preferred embodiment of the present invention. Probe  100  comprises an elongated body portion  101 , proximate end portion  103 , and distal end portion  105 . In the preferred embodiment, probe  100  comprises two support members or tubes  107 A and  107 B. Tubes  107 A and  107 B comprise elongated tube portions  109 A and  109 B and curved tube portions  111 A and  111 B. 
     In the preferred embodiments, elongated tube portions  109 A and  109 B of elongated body portion  101  define the longitudinal axis  113  of the probe. Elongated body portion  101  allows immersion of distal end portion  105  to the desired depth below surface  115  of a sample vessel  102 . Tube  107 A serves as a support member for transmitting optic fiber  117 A interior to tube  107 A. Likewise, tube  107 B serves as a support member for receiving optic fiber  117 B interior to tube  107 B. 
     In the preferred embodiments, curved tube portion  111 A bends approximately 90 degrees toward tube  107 B and curved tube portion  111 B bends approximately 90 degrees toward tube portion  111 A to define a sample gap  119  between respective distal tube ends  121 A and  121 B. 
     In the preferred embodiments, tubes  107 A and  107 B are connected by upper alignment member or cross-member  123  and lower alignment member or cross-member  125 . Cross members  123  and  125  provide structural support for tubes  107 A and  107 B and provide alignment between optic fiber ends as shown in FIG.  2 . 
     FIG. 2 is a detailed front view cross-section of sample gap  119  area of the optic fiber probe  100  showing optic surface  203 A of transmitting optic fiber  117 A supported at distal tube end  121 A and optic surface  203 B of receiving optic fiber  117 B supported at distal tube end  121 B. Lower cross member  125  supports curved tube portions  111 A and  111 B so that longitudinal or optic axis  205 A of transmitting optic fiber  117 A and longitudinal or optic axis  205 B of receiving optic fiber  117 B are aligned with gap width  207  between optic surface  203 A and optic surface  203 B. In the preferred embodiments, cross-member  125  supports curved tube end portions  111 A and  111 B so that longitudinal axes  205 A and  205 B are parallel. In the most preferred embodiments, longitudinal axes  205 A and  205 B are coincident. 
     Sample gap  119  provides a direct path for electromagnetic wave communication between transmitting optic fiber  117 A and receiving optic fiber  117 B, without path-altering optic elements such as mirrors or prisms. In the preferred embodiments, the electromagnetic communication is light and in the more preferred embodiments, the electromagnetic communication is UV wavelength light. Disposing the optic axis (longitudinal axis of the sample gap  119 ) perpendicular to longitudinal axis  113  of the probe minimizes entrapment of air bubbles or debris on surfaces of the probe in the gap area which might otherwise interfere with the electromagnetic wave communication between the optic fibers. 
     In the preferred embodiments, the submerged portions of support tubes  107 A and  107 B such as curved tube portions  111 A and  111 B are small diameter tubes having close fit tolerances with interior optic fibers  117 A and  117 B. Support tubes  107 A,  107 B, and tube portions  111 A and  111 B are selected to have a diameter as small as practical to reduce flow dynamic disturbances during tablet dissolution tests. 
     In the preferred embodiments, optic fibers of diameters of 200-600 micrometers offer a balance of adequate throughput, flexibility, minimum radius of curvature and minimum size for low flow resistance. In the more preferred embodiments, optic fibers  117 A and  117 B are less than 350 micrometers. A particularly preferred embodiment utilizes 200-300 micrometer fibers such as 300 micrometer optic fibers that efficiently transmit UV light over the wavelength range of 200 to 400 nanometers. 
     Submerged portions of the tubes must provide adequate strength and support for the fibers with minimum outside diameter for reduced effects on fluid flow in the sample vessel and in the sample area. In the preferred embodiments, support tube members  107 A and  107 B are 16-24 gauge stainless steel tubing. In the more preferred embodiments, support tubes  107 A and  107 B are 22 gauge (0.028″ OD, 0.016″ ID) type 316WSS hypo tubing, standard wall. In the preferred embodiments, the support tube diameter  210  of the submerged tube portions such as elongated body portion  101  and distal end portion  105  is less than 2.0 mm in order to reduce fluid flow effects in the vessel and sample area. In the more preferred embodiments, the support tube diameter of the submerged portions is less than 1.5 mm. In the most preferred embodiments, the support tube diameter at the distal end portion  105  is less than 1.0 mm. 
     In the preferred embodiments, the support tube diameter at the distal end portion  105  is less than 0.05 of probe length  131  to reduce fluid flow effects in the active sample area. In the more preferred embodiments, the support tube diameter at the distal end portion  105  is less than 0.02 of probe length  131 . In the most preferred embodiments, the support tube diameter at the distal end portion  105  is less than 0.01 of probe length  131 . 
     Reduction of the displaced volume of the submerged portions of the probe also reduces flow disturbances resulting from the probe. In the preferred embodiments, the displaced volume of the submerged portion of probe  100  is less than 200 cubic millimeters. In the more preferred embodiments, the displaced volume of probe  100  is less than 100 cubic millimeters. In the most preferred embodiments, the displaced volume of probe  100  is less than 50 cubic millimeters. The displaced volume of the submerged portion of support tubes  107 A and  107 B is defined as the volume of the portions of probe  100  of FIG. 1 below surface  115  when the probe is positioned in a vessel for dissolution testing purposes. 
     It is understood that modifications to the embodiments shown, such as non-circular tube cross-sections may be used which are within the scope of the invention. For non-circular cross sections, the effective diameter of the non-circular section is defined as: 
     
       
           D ( eff )=1.273× A    
       
     
     Where A is the cross-sectional area of the non-circular cross-section. 
     In the preferred embodiments, the effective diameter of lower cross-member  125  is dimensioned to the same criteria of support tube diameter  210  at distal end  105  to reduce flow disturbances and to reduce surface area in the sample gap region that would collect residue and bubbles during tablet dissolution events. In the preferred embodiments, no optic elements such as prisms or mirrors are utilized, for example, to produce multiple light path directions in the sample gap area. Such elements increase flow disturbances and increase surface area which might accumulate debris and bubbles during sampling evolutions. A direct light path as shown in FIG. 2 provides a light-efficient gap, allowing small-diameter fibers and support tubes to be used to decrease flow disturbances in the sample gap and surrounding area of the vessel. 
     FIG. 3 is a front elevation drawing of an optic probe assembly  300  inserted into sample vessel  302 . Probe assembly  300  comprises an upper support assembly  301  fixed to an optic probe portion such as optic probe  100  of FIG.  1 . Upper support assembly  301  comprises connection tubes  303 A and  303 B that fit over support tube members  107 A and  107 B of proximate end portion  103  of FIG.  1 . 
     Connection tubes  303 A and  303 B comprises bend portions  305 A and  305 B which provide offset handle portions  307 A and  3307 B. Handle portions  307 A and  307 B comprise optic fiber connectors  309 A and  309 B for connecting optic fibers  311 A and  311 B from the instrumentation to optic fibers  117 A and  117 B of optic probe section  100 . Probe clamp  315  of vessel cover  317  clamps probe assembly  300  and allows adjustment such as sampling height  319  of sample gap  119 . Paddle assembly  321  and shaft  323 , shown in phantom lines, provides desired fluid agitation in vessel  302 . 
     FIG. 4 is a side elevation drawing of optic probe assembly  300  in vessel  302 . Bend portions  305 A and  305 B provide offset handle portion  307 A and  307 B to assist in inserting, withdrawing and adjusting the position of the probe within sample vessel  302 . Bend portions  305 A and  305 B also minimize possible interferences with paddle drive components that are part of commercial test equipment. 
     In assembling of the preferred embodiments, a length of fiber (longer than the total length of the support tube member) is inserted into the curved tube portion and epoxied into place at the light path gap end. The fiber end may be either flush with the tube end or slightly extended with epoxy around the edges forming a sloping mound around the exposed fiber. 
     The preferred assembly method results in a polished fiber end that is flush with the tube end. The fiber end may be polished before or after inserting the fiber into the tubing. The preferred assembly procedure is to insert a length of fiber into the distal end of the tube. For large (greater than 5 mm.) sample gaps, the distal fiber end can be polished after being epoxied into place. For smaller sample gaps, the distal fiber end can be prepolished before inserting into the distal end of the tube. If the distal fiber end is polished after insertion, the fiber may be inserted at either the proximal or distal ends. The objective is to avoid damaging the distal fiber end. 
     The tubes of upper support assembly  301  are inserted over the fibers and attached to the elongated tube portions of probe  100  with epoxy. The upper fiber ends are prepared for termination in the SMA connector. These fiber-to-connector termination procedures, though non-trivial, are well known and routinely employed in the telecommunications industry. The SMA (or other) connector is inserted over the fiber and attached to the upper support assembly with epoxy. Epoxy is also applied inside the ferrule. The epoxy is allowed to dry and the final polish is applied to the SMA terminated fiber. 
     In other embodiments and assembly procedures, no connectors are used at the probe and the fibers are terminated at the spectrograph and the light source. 
     In the preferred embodiments, an adjustable probe holder or clamp  315 , inserted in aperture or slot  317 A of vessel cover  317  secures probe assembly  300  to vessel cover  317 . Probe assembly  300  is secured by clamp screw  325  and nut  327  to grip connection tubes  303 A and  303 B, and provide a means to adjust the sample gap depth  319  in sample vessel  302 . Vessel cover  317  comprises slot  317 B for insertion of shaft  323  of paddle assembly  321 . The operator will adjust he holder position depending on dissolution bath type, solution volume and vessel size. 
     Adhesives such as epoxy may be used to fix connection tubes  303 A and  303 B of upper support assembly  501  to optic probe section  100  at tube ends  331 . Alternatively, welding or mechanical fasteners may fix upper support assembly  501  to optic probe section  100 . Adhesives such as epoxies may also secure optic fibers  117 A and  117 B in tube members  107 A and  107 B at tube end  333 . Adhesives such as epoxies may be used to secure optic fibers  311 A and  311 B in tubes  303 A and  303 B of upper support assembly  501 . Optic connector  509  may be an optic connector known in the art such as an SMA type connector. 
     FIG. 5 is a schematic diagram of a multi-channel, fiber optic-based UV spectrometer system  501  optimized for measuring the dissolution rates of pharmaceutical dosage forms. The basic measurement principle is identical to conventional UV spectroscopy, wherein dissolved component concentrations are proportional to the amount of light absorbed by the sample. 
     Multiple fiber optic probes, such as fiber optic probe  300  are illuminated with UV light through transmitting optic fibers  311 A terminated at a low-noise deuterium light source  511 . 
     Light passing through the sample gap  119  of probe  300  passes through receiving optic fibers  311 B terminated at the inlet slit  518  to spectrograph  519 . The spectrograph separates light into different wavelengths and simultaneously images the light beams onto a charge coupled device (CCD) detector. 
     Light intensity data is transferred to the computer  521 , where software calculates and displays absorbance values and percent dissolved for each channel at user-selected time points and wavelengths. Controller  523  interfaces with computer  521  and provides control of light source  511  and spectrograph  519 . Paddle assembly  321  provides desired agitation in vessel  302  as described previously. The lower end of the shaft is threaded to accept baskets and tablet dies used for intrinsic dissolution testing. 
     Ten or more vessels can be monitored simultaneously by coupling receiving fibers  311 B to the CCD of spectrograph  519 . Coupling ten or more probes such as probe  300  to a single CCD of a spectrograph is made possible by the efficient direct light path in sample gap  119  of probe  300 . The direct light path allows small-diameter receiving fibers and hence a higher density of receiving fibers scanned by the CCD of spectrograph  519  than would be possible utilizing conventional probes utilizing additional optic elements such as mirrors, prisms, etc. The actual image acquisition time depends on the user-selected exposure or integration time (typically 100-1000 ms). In another preferred embodiment, at least 12 receiving fibers from sample vessels are monitored by a single spectrograph. In still another embodiment, at least 18 receiving fibers from sample vessels are monitored by a single spectrograph. 
     At each user-selected time point, the system software acquires and saves complete UV spectra for all configured channels. The collected data at a given time point is referred to as a “data set”. The effect of different analytical wavelengths and/or baseline correction techniques can be immediately observed by changing the desired parameters. 
     Reference blank intensity spectra are acquired for both sample and standard blank solutions prior to the dissolution test. Prior to all image acquisitions the software automatically acquires a background or “dark current” reading that is subtracted from the light intensity reading. Since the background reading also contains a room light component, all light intensity and absorbance values are also corrected for any room light that may be entering through the fiber optic probes. The actual time required to acquire the background and sample intensities and transfer the data to the computer is typically 8-15 sec. This represents the minimum time between sample measurements. 
     Percent dissolved calculations are based on measurements of standard solutions and the expected amount of the target ingredient in the sample. The software has different options for correcting both sample and standard absorbance values for baseline variations related to turbidity, source drift, or light scattering. 
     FIGS. 6A-6D show alternative embodiments of optic probes which reduce hydraulic flow disturbances in a sample gap portion of the probe. In each of these embodiments, the longitudinal axis of the probe is defined by the elongated body portion of the probe. The longitudinal axis of the probe will normally be perpendicular to the surface of the fluid in a sample vessel. 
     The elongated tube portion  609 A of probe  600 A comprises two elongated tubes  607 A 1  and  607 A 2 , attached by welding, adhesives or mechanical fasteners. Tube portions  607 A 1  and  607 A 2  support optic fibers  617 A 1  and  617 A 2 . Curved tube portions  611 A 1  and  611 A 2  comprise compound, “C” or “S” type bends to form sample gap  619 A of length  633 A perpendicular to longitudinal axis  613 A. The curved tube portions may be symmetric as shown, or they may be non-symmetric. The diameter of lower curved tube portions  611 A 1  and  611 A 2  are small as compared to probe length  631 A and follow the absolute dimensions as discussed in embodiment  100  of the optic probe to reduce hydraulic flow disturbances of the sample fluid, for example during tablet dissolution testing. 
     FIG. 6B shows a variation  600 B of embodiment  100  of the optic probe wherein elongated tube portions  609 B 1  and  609 B 2  of support tube members  607 B 1  and  607 B 2  are angled or “fanned” outward with respect to each other and longitudinal axis  613 B from the distal to the proximal end of the probe. The angling out of the proximal ends of the elongated tube portions allows curved tube portions  611 B 1  and  611 B 2  to be less than 90 degrees, improving light transmission efficiency of the optic fibers. In other embodiments, only one elongated tube portion is angled out with respect to longitudinal axis  613 B. In the preferred embodiments, sample gap  619 B, of length  633 B, is perpendicular to longitudinal axis  613 B. The diameter of lower curved tube portions  611 B 1  and  611 B 2  are small as compared to probe length  631 B and consistent with absolute dimensions as discussed in embodiment  100  of the optic probe to reduce hydraulic flow disturbances of the fluid, for example during tablet dissolution testing. 
     FIG. 6C shows an alternative embodiment of “U”-shaped optic probe  600 C having one support tube member  607 C 1  having a curved, substantially “J” shape and the second support tube member  607 C 2  substantially straight. This embodiment results in longitudinal axis of sample gap  619 C, of length  633 C, being approximately parallel to longitudinal axis  613 C. The diameter of lower curved tube portion  611 C 1  and lower tube portion  611 C 2  are small as compared to probe length  631 C and consistent with absolute dimensions as discussed in embodiment  100  of the optic probe to reduce hydraulic flow disturbances of the fluid, for example during tablet dissolution testing. 
     FIG. 6D is an embodiment  600 D of the optic probe similar to that of FIG. 6A except that elongated body portion  601 D and extended leg portions  611 D 1  and  611 D 2  form an integral body assembly  641 . Sample gap  619 D, of length  633 D, is perpendicular to longitudinal axis  613 D. The diameter of extended leg portions  611 D 1  and  611 D 2  are small as compared to probe length  631 D and consistent with absolute dimensions as discussed in embodiment  100  of the optic probe to reduce hydraulic flow disturbances of the fluid, for example during tablet dissolution testing. 
     In the preferred embodiments, a length of fiber (longer than total length of the support tube member) is inserted into the bent leg and epoxied into place at the light path gap end. The fiber end may be either flush with the tube end or slightly extended with epoxy around the edges forming a sloping mound around the exposed fiber. The fiber is then polished. This is repeated for both legs. 
     The tubes of upper support assembly  301  of FIG. 3 are inserted over the fibers and attached to the elongated tube portions of probe  100  with epoxy. The upper fiber ends are prepared for termination in the SMA connector. These fiber-to-connector termination procedures, though non-trivial, are well known and routinely employed in the telecommunications industry. The SMA (or other) connector is inserted over the fiber and attached to the upper support assembly with epoxy. Epoxy is also applied inside the ferrule. The epoxy is allowed to dry and the final polish is applied to the SMA terminated fiber. In other embodiments, the fibers are jacketed with flexible material routinely employed in the art and terminated using industry standard connectors directly to the light source and detector. 
     Other embodiments of the optic probe may utilize multiple transmitting or receiving optic fibers. Yet other embodiments may utilize relatively larger diameter receiving optic fibers, and its support tube in relation to the transmitting optic fibers and its support tube. For example, in the embodiment of FIG. 6C, fiber  617 C 2  may be selected as the receiving fiber and be a larger diameter fiber than transmitting fiber  617 C 1  in order to supply a larger amount of light energy at sample gap  619 C. The higher light efficiency of sample gap  619 C allows a smaller diameter fiber  617 C 1  and a relatively small bending radius of lower tube portion  611 C 1 . Upper support assemblies, such as that shown in FIG. 5, may be utilized with these or equivalent probes, modified as required. 
     Accordingly, the reader will see that the fiber optic probe of the present invention provides an in vitro pharmaceutical dissolution testing optic fiber probe which improves performance and consistency of tablet dissolution testing. The device provides the following additional advantages: 
     The probe utilizes a direct light path without redirecting the light path with mirrors, prisms or other supplementary optic elements; 
     The probe reduced-diameter transmitting and receiving optic fibers allowed by the increase in optic efficiency of the direct light path gap, allows reduced-diameter probe components such as fiber support tubes and reduced hydraulic disturbances resulting from the smaller probe elements; 
     The reduced-diameter receiving fibers allow more channels of sample probes analyzed by a single CCD of a spectrograph; and 
     The optic probes and dissolution test systems are simple and low in cost. 
     Although the description above contains many specifications, these should not be construed as limiting the scope of the invention but merely providing illustrations of some of the presently preferred embodiments of this invention. Thus the scope of the invention should be determined by the appended claims and their legal equivalents, rather than by the examples given.