APPARATUS AND METHODS TO MEASURE OPTICAL ROTATION WITH ELECTRO-OPTIC POLARIZATION MODULATION

TECHNICAL FIELD

[0001 ] The present invention relates to an apparatus and method for measuring optical rotation, and in particular an apparatus and method for measuring optical rotation with electro-optic polarization modulation.

BACKGROUND ART

[0002] Many chemical compounds, including most biologically active compounds, exist in two different forms, called enantiomers that rotate the plane of linearly polarized light in opposite directions. Such compounds are also referred to as chiral compounds. The ability to rotate the orientation of linearly polarized light is one of the manifestations of optical activity. Instruments to measure optical rotation (OR) are commonly referred to as "polarimeters".

[0003] Many polarimeters employ either a mechanically rotated polarizer or nulling Faraday rotator, and measure DC signal as a function of, respectively, polarizer rotation angle or current applied to the Faraday rotator to determine the magnitude of optical rotation. The techniques based on DC signal measurements suffer from relatively low accuracy, sensitivity and measurement speed.

[0004] A different kind of apparatus based on mechanical rotation is described by Gundermann in United States Patent Number 4,118,125. In Gundermann, a continuously rotating polarizer, driven synchronously with digital clock pulses, analyzes the light that passes through the sample. The phase of the signal generated by the detector is then compared to the phase of a digital reference signal derived from the clock pulses to determine the optical activity of the sample.

[0005] An apparatus designed to measure glucose concentration in an eye is described by Cote et al. in United States Patent Number 5,209,231. In Cote, a circularly polarized beam passes through a rotating polarizer and then through a sample. The Cote design requires the use of two photodetectors and the optical rotation of the sample is obtained from the difference between the phase of the time-varying signal that is measured by the first detector prior to the sample and the phase of the time- varying signal produced by the second detector, measured after the sample.

[0006] Polarimeters that are based on electro-optical polarization modulation and lock-in detection of the signal modulation amplitude (AC signal) offer a more sensitive and faster alternative to the methods that are based on mechanical rotation and/or detection of a DC signal. Lock-in detection produces much higher sensitivity and signal-to-noise ratio than DC detection and electrooptic modulators offer faster modulation and better stability than mechanically-rotated optical components. Instruments based on lock-in detection typically use a polarization modulator, such as a Faraday rotator, to modulate the polarization. The optical activity detector by Yanik, described in United States Patent Number 5,822,067, uses a Faraday rotator, a laser diode and a lock-in amplifier. In this design, the current applied to the Faraday rotator oscillates at 500 Hz and the measured amplitude of the AC signal at 500 Hz is proportional to the amount of optical rotation in the sample. In United States Patent Number 5,012,101, Goodall et al. described an apparatus and method similar to those described by Yanik. In another design of a chiral detector (Chiralizer by IBZ Messtechnik), the amplitude of the AC current applied to a calibrated Faraday rotator is nulled or varied to bring the signal oscillation to zero. The amount of optical rotation is then determined from the residual current supplied to the Faraday rotator.

[0007] United States Patent Number 4,988,199 by Paul describes an apparatus and method where the concentration of optically active substances is determined by measuring the polarization of light passed through the substance using a Faraday rotator. The output signal from the detector is alternately integrated during each half period of the modulation frequency to form two voltage values, which are stored. The quotient of these stored voltage values is calculated and an adjustable constant voltage is subtracted from the quotient.

[0008] Alternative devices, which do not utilize polarization modulation with a Faraday rotator, do exist. For example, In United States Patent Number 5,477,327, Bergman describes a polarimeter where two linearly polarized beams at 45 degrees to each other are amplitude modulated at low frequency, with phases that are at 90 degrees to each other. After passing through a sample, the beams pass through a polarizing cube. The optical rotation is measured as a phase shift between the two separated orthogonal polarization components. Pezzaniti et al., in United States Patent Number 5,788,632, described an apparatus to measure concentration of an optically active compound in a biological sample that uses two rotating wave plates or two variable retarders (liquid crystal, electrooptic or other variable retarders) to produce the Mueller matrix of the

sample. In United States Patent Number 5,168,326, Tokieda et al. describes an apparatus and method where the polarization of a light beam is modulated between linear and circular states by a Pockels cell. The beam, which is subsequently transmitted through a sample solution in a flow cell, is separated into two polarized light components, and a signal corresponding to an angle of rotation is obtained by subtracting the signal obtained during irradiation of the sample with circularly polarized light from the signal obtained during irradiation of the sample with the linearly polarized light. The Tokieda apparatus, however, employs two separate detectors and does not utilize phase-sensitive (lock-in) detection. Instead, an electronic calculator that simply subtracts the signals, obtained at the two polarization states (linear and circular) generated by the Pockels cell, is used. The present invention is directed toward overcoming shortcomings in prior art devices.

SUMMARY OF THE INVENTION

[0009] One aspect of the present invention is an optical rotation measuring apparatus including a light source positioned to transmit light through a first polarizer which is in optical communication with the light source. Also included is a sample cell suitable for holding a chiral compound for analysis. The sample cell is positioned to receive light transmitted through the first polarizer from the light source. The optical rotation measuring apparatus also includes an electro-optic modulator receiving light transmitted through the sample cell and an analyzer receiving light transmitted through the electro- optic modulator. In addition, the optical rotation measuring apparatus includes a photodetector receiving light transmitted through the analyzer.

[0010] The electro-optic modulator of the present optical rotation measuring apparatus may be any electro-optic modulator, however, a Pockels cell, photoelastic cell modulator, liquid crystal cell modulator, or Kerr cell modulator would be particularly well suited for the implementation of the present apparatus. A nonresonant Pockels cell having an electro-optic material, which might be lithium niobate crystal, Potassium Dihydrogen Phosphate (KDP), Potassium Dideuterium Phosphate (KD*P), Ammonium Dihydrogen Phosphate (ADP), Rubidium Titanyl Phosphate (RTP), Beta-Barium Borate (BBO), opto- ceramic material or an electro-optic polymer, is favored for use as the electro-optic modulator of the present optical rotation measuring apparatus.

[001 1] The optical rotation measuring apparatus may include a modular and replaceable photodetector, analyzer, polarizer, and light source. The photodetector may be any type of photodetector, however, a photodiode, photomultiplier, CCD detector array, and

CMOS detector array are particularly well suited for implementation of the invention. The analyzer may be a second polarizer. The analyzer and the polarizer may be of any type, however, a crystal polarizer, a dichroic polarizer, a tipped plate polarizer, a thin film polarizer, a liquid crystal polarizer, or a wire grid polarizer may all be used to implement the present invention. The light source may be of any type, however, a laser, a light emitting diode (LED), an incandescent light source, or an arc lamp are particularly well suited for implementation of the present invention.

[0012] The photodetector may be a single element or the detector may be an array of more than one photodetector for the detection of more than one range of light wavelength.

[0013] The optical rotation measuring apparatus may also include a controller operatively associated with the electro-optic modulator. The controller may include a lock-in amplifier. The lock-in amplifier features phase sensitive detection and may include a digitally controlled analog amplifier with internal digitization of the amplifier analog output.

[0014] Another aspect of the present invention is a method of measuring optical rotation including transmitting light from a light source through a first polarizer, transmitting the polarized light from the first polarizer through a sample cell containing a chiral compound, and transmitting light from the sample cell through an electro-optical modulator. The method of measuring optical rotation further includes transmitting light from the electro-optical modulator through an analyzer, receiving light from the analyzer with a photodetector, and measuring optical rotation as a function of the amplitude of the intensity modulation of the light received by the photodetector.

[0015] The method of measuring optical rotation may include aligning the fast axis of the electro-optical modulator parallel to the transmission axis of the first polarizer. In addition, the transmission axis of the analyzer may be aligned at about a 45° angle from the transmission axis of the first polarizer. Alternating current may be applied to the electro-optical modulator having a frequency greater than 1 kHz.

[0016] The method of measuring optical rotation may include selecting the modulation of the electro-optical modulator to alternate the optical retardance produced by the modulator between about 0 and about one half of the wavelength of the light transmitted from the light source. Alternatively, the modulation of the electro-optic modulator may be selected to alternate the optical retardance produced by the modulator between two values differing by about one half wave at the wavelength of the light transmitted from the light source.

[0017] The amplitude of the intensity modulation of the light received by the photodetector may be measured with a phase sensitive lock-in amplifier.

BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIG. 1 is a schematic diagram of one embodiment of the present invention.

[0019] FIG. 2 is a drawing of a coordinate system defining the orientation angles of the optical components of the present invention.

[0020] FIG. 3 is a schematic diagram of the electric field vector of light in the electro- optic modulator of the present invention.

[0021] FIG. 4 is a set of two graphs concerning the estimated sensitivity of the apparatus and methods provided herein.

[0022] FIG. 5 is a schematic diagram of the optical layout of another embodiment of the present invention.

[0023] FIG. 6 is a schematic diagram of the optical layout of another embodiment of the present invention.

[0024] FIG. 7 is a schematic diagram of the optical layout of another embodiment of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT [0025] The present invention includes an optical rotation measuring apparatus (OR- meter) 10 including one or more electro-optic modulators for polarization modulation, at least two polarizers, or a polarizer and an optical retarder, and optionally including an integrated lock-in amplifier. The OR-meter 10 may also include a connection, such as a USB connection, to a virtual front panel on a host computer. The invention also includes methods for measuring optical rotation using embodiments of the disclosed OR-meter. [0026] The measured optical rotation is proportional to the concentration of the optically active sample. OR-meters and methods according to the present invention may be used in numerous applications, including, but not limited to, concentration measurements in pharmaceutical, agrochemical, sugar and food & beverage industry. A particularly important application of polarimetry is in drug analysis, drug discovery, biochemical analysis, organic synthesis and natural product analysis. Polarimetry is useful for chiral (enantiomer-sensitive) detection in chromatography. Chiral detectors are sensitive to the signal polarity (i.e., the sense of optical rotation) and can distinguish between the two enantiomers by identifying corresponding positive and negative signals (chromatographic

peaks). When used with a flow cell, the OR-meters described herein can serve as a chiral detector for preparative chiral-phase high-performance liquid chromatography, gas chromatography, thin-layer chromatography, capillary electrophoresis or to determine the enantiomeric excess (relative content of the enantiomers) in a mixture of enantiomers. Another application of the present OR-meter and methods provided herein is noninvasive measurement and/or monitoring the level of glucose, fructose, glutamine, phenylalanine and other optically active compounds in blood or aqueous humors.

[0027] The OR-meter provided herein has a number of advantages over currently used polarimeters. One advantage is an increased sensitivity and measurement speed relative to polarimeters based on DC detection and/or mechanically-rotated polarization optics elements. Because the OR-meter provided herein uses phase-sensitive detection, further advantages over prior-art polarimeters that are based onfast polarization modulation and lock-in detection include, but are not limited to, better signal-to-noise performance and a higher rate of data acquisition than a Faraday rotator, liquid crystal, rotating polarizer orrotating wave plate, thereby allowing for fast sample flow-through operation and the monitoring of dynamic processes, such as the kinetics of chiral reactions, racemization or denaturation of proteins and fermentation. Another advantage of the OR-meter provided herein is the driving scheme and data reduction that maximize the sensitivity by maximizing the magnitude of the signal corresponding to the sample's optical rotation, measured with only a single detector. This is achieved by modulating the relative phase between the two orthogonal components of light by approximately half-wave or π radians. Further advantages will be apparent to those skilled in the art.

[0028] A schematic diagram of one embodiment of the present OR-meter 10 is shown in FIG. 1. In this configuration a light source 12, first polarizer 14, second polarizer or analyzer 16, a sample cell 18, an electro-optic modulator 20 and a photodetector 22 are mounted on a base plate 24. An electronics unit 26 is interfaced to a data processor, for example a personal computer 34, equipped with operation software and a user interface such as a graphical user interface. The electronics unit may include a lock-in amplifier 28, electro-optic modulator control electronics 30 and microcontroller-based controller electronics 32. The orientations of the fast axis of the electro-optic modulator and the transmission axis of the analyzer 16 may be, respectively, zero degrees and 45 degrees with respect to the transmission axis of the first polarizer 14.

[0029] The Cartesian right-handed XYZ coordinate system depicted in FIG. 2 can be used to define the orientation angles of the optical components 14, 16 and 20 shown in FIG. 1. The light from the source 12 propagates along the positive Z-axis 36. The orientation angles are defined with respect to the XZ-plane and measure from the X-axis 38 towards Y-axis 40, as indicated by an arrow 42. Since the orientation of the X-axis 38 is arbitrary, the orientation of the components 14, 16 and 20 can be rotated by the same, arbitrary angle. Although in certain embodiments a Pockels cell is used as the electro- optic modulator 20, other polarization or phase modulators can be used, such as photoelastic, liquid crystal or Kerr cell modulators. As used herein, however, an electro- optic modulator 20 does not include a Faraday rotator.

[0030] The light beam produced by the light source 12 and linearly polarized by the first polarizer 14 passes through the sample cell 18 containing an optically active sample and then passes through the electro-optic modulator 20, for example a Pockels cell. The light beam passes then through the analyzer 16 and the detector 22 measures its intensity. The modulated signal voltage produced by the detector 22 is sent to the lock-in amplifier 28. The Pockels cell controller 30 provides driving voltage to the Pockels cell and reference frequency to the lock-in amplifier 28.

[0031] A suitable light source 12 may include a variety of lasers, LED's, and incandescent and arc lamps. Additional collimating and/or beam shaping optics may be added as a part of the light source 12. Different applications require the use of different light sources because many standard optical activity measurements must be performed at specific wavelengths, for example at the sodium D-line wavelength, 589 nm. In one embodiment, the OR-meter 10 is equipped with a single laser diode or a high-power LED. The present invention may be assembled from apparatus user replaceable modular components. The modular design of the OR-meter 10 thus allows for the light source 12 to be replaced with one operating at different wavelength or wavelengths. In a multi- wavelength configuration, the OR-meter 10 may be implemented with mercury, halogen or tungsten lamp with a set of filters. When used as a chiral detector, the preferred light source is a blue, violet or ultraviolet diode laser or LED.

[0032] The type of the polarizer 14 and analyzer 16 used depends on wavelength of wavelengths of light transmitted from the light source 12. The analyzer 16 may simply be a second polarizer. The possible apparatus suitable for use as a polarizer 14 or analyzer 16 includes but is not limited to crystal (e.g., calcite), dichroic, tipped plate, thin film, liquid crystal, and wire-grid polarizers. Owing to the modular design of the OR-meter 10,

the less expensive dichroic or wire-grid polarizers suitable for use in the visible and near- infrared light wavelength ranges can be replaced as needed with more expensive calcite polarizers that operate in the ultraviolet wavelength range.

[0033] In one embodiment, the electro-optic modulator 20 is a nonresonant Pockels cell made of lithium niobate crystal that is suitable for use in the visible and near infrared range of the light spectrum. To expand the usable wavelength range, alternative embodiments may employ Pockels or other electro-optic modulators having other electro- optic materials that include but are not limited to Potassium Dihydrogen Phosphate (KDP), Potassium Dideuterium Phosphate (KD ⁺ P), Ammonium Dihydrogen Phosphate (ADP), Rubidium Titanyl Phosphate (RTP) or Beta-Barium Borate (BBO), optoceramic materials or electro-optic polymers. Alternatively, other polarization or phase modulators can be used, such as photoelastic, liquid crystal or a Kerr cell modulator. As used herein, an electro-optic modulator may not be a Faraday rotator.

[0034] The modular design of the present invention also allows for easy switching and replacement of the photodetector 22 for different wavelength ranges. To cover the wavelength range from 325 nm to near infrared, three different photodiodes may be used: Shottky GaN photodiode for the 320 - 400 nm range or SiC detector for 210 - 380 nm; silicon photodiode for 400 - 1000 nm and GaAs photodiode for the wavelengths above 1000 nm. For increased versatility, an array of dual or multiple detectors, such as silicon and GaAs detectors may be used. In addition, a photomultiplier tube can be used. The photodetector or array may be of any suitable type including photodiodes, photomultipliers, CCD or CMOS detectors.

[0035] In one embodiment, a lock-in amplifier 28 is integrated with the control electronics 26. The lock-in amplifier 28 preferably uses microcontroller technology and is preferably designed specifically for the OR-meter 10. In one embodiment, the lock-in amplifier 28 is a digitally controlled analog amplifier with internal digitization of amplifier analog output. Such an integrated lock-in amplifier 28 offers competitive performance to high-end standalone lock-in amplifiers for less cost.

[0036] The operational software and graphical or other user interface on the data processing system or computer 34 can be, but is not required to be, an integral component of the OR-meter apparatus. Data acquisition is preferably partially programmed into the microcontroller, and the experimental data is preferably sent to the host computer 34 via, for example, a USB interface, and processed by the operation software on the host computer 34. The various control parameters, such as operating wavelength, operation

mode, sampling parameters and lock-in detector settings are preferably all programmable from the front panel; parameters may be validated and checked for self-consistency and then sent via a USB message pipe to the microcontroller 32. Digitized output can be continuously sent back to the host 34 via a separate interface, such as a USB stream pipe. In one embodiment, the OR-meter 10 is equipped with a National Instruments Lab VIEW virtual front panel on the host computer 34. In alternative embodiments, the front panel and operation software can be written in programming languages other than Lab VIEW.

[0037] Referring to the embodiment depicted in FIG. 1, a light beam generated by a source 12 passes through a first polarizer 14 having its transmission axis oriented at an arbitrarily designated zero degrees. The light is then passed through a sample cell 18 with an optically active sample to be measured. Subsequently, the light is passed through an electro-optical modulator 20, such as a Pockels cell, which has its fast axis aligned parallel to the transmission axis of the first polarizer 14. Due to the geometry of a typical Pockels cell's housing, it is convenient (but not necessary) to set the X-axis 38 defined in FIG. 2 to be horizontal or parallel to the mounting base 7. The voltage applied to the Pockels cell 20 is modulated at a frequency greater than 1 kHz. The Pockels cell modulation alternates its optical retardance in, for example, a sinusoidal or step pattern, between two values, the first of which is zero and the second is half- wave or τ radians at the wavelength of the light used in the measurement. The light is then passed through an analyzer 16, which has its transmission axis oriented at 45 degrees relative to the transmission axis of the polarizer 14. Subsequently, the beam strikes a photodetector 22. The photocurrent having an intensity modulation with measurable amplitude can but does not have to be converted to voltage and the resulting voltage or photocurrent may be amplified. The amplified voltage or photocurrent is sent as a signal to the lock-in amplifier 28, which detects and measures the desired AC component of the signal. A Pockels cell controller 30 provides the reference signal for the lock-in amplifier 28. If desired, an integrating or low-pass filter can be used to recover the average DC signal for light power normalization or correction.

[0038] In the absence of optical rotation, there is no intensity modulation on the output beam because the polarization of the light emerging from the sample cell 18 is parallel to the optical axis of the modulator 20, and the modulator 20 thus does not modulate the polarization of the beam. This situation is illustrated in FIG. 3A, which shows an X-Y plane cross section 44 of the Pockels cell crystal. As described above, the Pockels cell crystal is oriented at 0 degrees, that is, its fast axis is parallel to the X-axis 38 of the

coordinate system defined in FIG. 2. The electric field vector 46 of light, which determines the polarization, is also parallel to the X-axis 38, and has no projection on the Y-axis 40.

[0039] When optical rotation is present, the polarization of light emerging from the sample cell 18 is no longer parallel to the optical axis of the modulator 20. This situation is illustrated in FIG. 3B. The electric field vector 46 is oriented at the angle a to the X- axis 38 after it has been rotated by the sample. In this case, a time-dependent phase shift is introduced between the X-component 48 and the Y-component 50 of the electric field vector 46 and the beam becomes polarization-modulated. After passing through the analyzer 16 oriented at 45 degrees to the X-axis 38, the polarization-modulated beam becomes intensity-modulated. The amplitude of this intensity modulation, which is measured by the lock-in amplifier 28, depends on the optical rotation angle a.

[0040] The time-varying signal intensity S[cc, F(Z)] measured by the detector 22 is proportional to

I^ + sin α cos α cos F(O = K (l + sin 2α cosr(Y)) (1) where t is time and V(t) is the time-dependent retardance modulated by the Pockels cell (modulator 20). Since the retardance of the Pockels cell varies between zero and τ radians (half-wave), the demodulated AC signal extracted by the lock-in amplifier 28 is where K is an instrument-dependent constant. The instrument calibration is then used to obtain the constant K. For an ideal apparatus, when the signal measured by the detector 22 in the absence of optical rotation is normalized to unity, the calculated magnitude of modulation, as measured by the lock-in amplifier 28, is approximately 3.5 x 10 ^'5 for a = 1 milliradian and 3.2 x 10 ^'7 for a= 0.01 milliradian.

[0041 ] When the specific rotation [a] _\ of the sample is known, a can be easily converted to concentration using the Biot's formula:

100 where C is the compound's concentration in g mL ^"1 and / is the light path length in the sample in dm. The subscript λ indicates the measurement wavelength.

[0042] The graph 52 of FIG. 4 shows the expected response of the apparatus 10 as a function of the optical rotation angle a. The resolution of the apparatus should decrease as a approaches 45°. For 45 deg < α < 90 deg the instrument response should mirror that

of the 0 deg < a < 45 deg range. Most of the common pharmaceutical OR measurements take place within the ± 10° range. The graph 54 in FIG. 4 demonstrates that, for 0 deg < o: < 10 deg, the response of the instrument is expected to be perfectly linear, with the correlation coefficient R equal 1.0000 (for 0 deg ≤a <20 deg, R=0.9996). In this range, the slope of the response curve is 0.03449 (± 1 x 10 ^"6 ) deg ^'1 .

[0043] FIG. 5 shows a schematic diagram of the optical layout of a further embodiment. In this configuration, an additional retarder (wave plate) 56 is placed in the optical path. The optical components are arranged in the following order: the light source 12, the first polarizer 14 oriented at zero degrees, the sample cell 18, the electro-optic modulator 20 oriented at zero degrees, the retarder 56 oriented at 45 degrees, the analyzer 16 oriented at zero degrees, and photodetector 22. The optical retardance of the electro-optic modulator 20 is modulated between the two values, the first of which is negative quarter-wave or - τ/2 radians and the second is positive quarter- wave or τ/2 radians at the wavelength of the light used in the measurement. When the retardance value of the retarder 56 is quarter- wave or τ/2 radians, the time-varying signal intensity measured at the detector 6 is proportional to

YJ + sin a cos a sin T(t) (4)

[0044] FIG. 6 shows a schematic diagram of the optical layout of another embodiment. In this configuration, the additional retarder (wave plate) 56 is placed in the optical path at a different position. The optical component are arranged in the following order: the light source 12, the first polarizer 14 oriented at zero degrees, the sample cell 18, the retarder 56 oriented at 90 degrees, the electro-optic modulator 20 oriented at 45 degrees, the analyzer 16 oriented at 90 degrees, and the photodetector 22. The optical retardance of the electro-optic modulator 20 is modulated between the two values, the first of which is negative quarter-wave or -ττ/2 radians and the second is positive quarter-wave or x/2 radians at the wavelength of the light used in the measurement. When the retardance value of the retarder 56 is quarter-wave or τr/2 radians, the time-varying signal intensity measured at the detector 22 is proportional to sin(α + r72) ² (5)

[0045] FIG. 7 shows a schematic diagram of the optical layout of a further embodiment. In this configuration, the additional retarder (wave plate) 56 is placed in the optical path at a different location. The optical component are arranged in the following order: the light source 12, the first polarizer 14 oriented at 45 degrees, the electro-optic modulator

20 oriented at 45 degrees, the retarder 56 oriented at 90 degrees, the sample cell 18, the analyzer 16 oriented at 90 degrees, and the photodetector 22. The optical retardance of the electro-optic modulator 20 is modulated between the two values, the first of which is 0 radians and the second is half-wave or τ radians at the wavelength of the light used in the measurement. When the retardance value of the retarder 56 is quarter-wave or τ/2 radians, the time-varying signal intensity measured by at detector 22 is proportional to

[0046] In Equations 4, 5 and 6, / is time and T(t) is the time-dependent retardance modulated by the electro-optic modulator 20. The theoretical sensitivities and measurement ranges are identical for both the embodiment in FIG. 1 and the three embodiments of FIG. 5, FIG. 6 and FIG. 7.

[0047] The two embodiments of FIG. 5 and FIG. 7 require the electrooptic modulator 20 to modulate the retardance between negative quarter-wave or -τ/2 radians and positive quarter- wave or τ/2 radians at the wavelength of the light used in the measurement. This can be accomplished with a standard photoelastic modulator or a Pockels cell equipped with an additional compensating quarter-wave plate placed after the modulator 20, to offset the retardances generated by the modulator 20 from -τr/2 and +τr/2 radians to 0 to 3τr/2 radians.

[0048] This can also be accomplished with a pair of Pockels cells oriented with their fast axes being orthogonal, and driven τ radians out-of-phase to each other.

[0049] Other modifications and extensions of the basic configurations, shown in FIG. 1, FIG. 5, FIG. 6 and FIG. 7, include, but are not limited to:

• Configurations with an additional beam splitter that can but does not have to be located between the source 1 and the polarizer 2, and an additional detector to detect a portion of the light picked-up by the beam splitter. The beam splitter and the additional detector can be used to monitor the fluctuations of light produced by the light source 12 and to normalize or correct the signal measured on the detector 22 for these light fluctuations.

• Configurations that use more than one electro-optic modulator to correct for temperature fluctuations or optical side band generation. Multi-wavelength configurations accommodating different combinations of light sources, polarization optics, filters and detectors for determination

of optical rotation of samples in presence of interfering optically-active or birefringent substances, or for the motion artifacts correction.

• Multi-wavelength versions for simultaneous measurement of optical rotation of unknown materials at multiple wavelengths.

• Instrument equipped with a spectrometer or a photodetector array to measure optical rotary dispersion spectrum. 0] While the invention has been particularly shown and described with reference to a number of embodiments, it would be understood by those skilled in the art that changes in the form and details may be made to the various embodiments disclosed herein without departing from the spirit and scope of the invention and that the various embodiments disclosed herein are not intended to act as limitations on the scope of the claims.