Glabridin-betaine eutectic crystal as well as preparation method and application thereof

Abstract

The invention discloses a glabridin-betaine eutectic crystal and a preparation method and application thereof, and belongs to the technical field of eutectic crystals, the eutectic crystal comprises betaine and glabridin molecules, the molecular formula of the glabridin-betaine eutectic crystal is C45H51NO10, the molar ratio of the betaine to the glabridin is 1: 2, and the molecular formula of the glabridin-betaine eutectic crystal is C45H51NO10. The betaine and the glabridin molecules are connected with each other through hydrogen-bond interaction. Complete characterization of the eutectic proves that the eutectic has high chemical purity and chemical stability, and compared with a betaine monomer, the eutectic shows excellent solid stability under a high humidity condition. And the eutectic crystal is generally neutral, mild, non-irritant, natural and suitable for cosmetics or health care products.

Description

Technical Field

[0001] This invention relates to the field of eutectic technology, specifically to a glycyrrhizin-betaine eutectic, its preparation method, and its uses. Background Technology

[0002] Betaine is a quaternary ammonium-type water-soluble alkaloid derived from sugar beets. It is an intermediate product of animal metabolism and is widely found in nature, playing a vital role in nutrient metabolism. The molecular structure of betaine contains both anionic and cationic charges within a single molecule. Since human skin is entirely negatively charged under normal physiological conditions, molecules containing positive charges have a natural affinity for the skin, enhancing its moisture, elasticity, and hydration, making it particularly suitable for skincare products. However, betaine is hygroscopic under high humidity conditions, posing risks during storage and transportation.

[0003] Glycyrrhizin is highly regarded for its excellent antioxidant, anti-aging, anti-inflammatory, and skin-brightening effects. However, its poor solubility and stability limit its application in cosmetics.

[0004] Cocrystallization is a method of forming crystalline materials by combining two or more different molecules through intermolecular interactions such as hydrogen bonds, π-π interactions, and van der Waals forces, resulting in a regularly arranged crystalline material within the same crystal lattice. Compared to monomers, cocrystallization can alter the physicochemical properties of a substance, such as solubility, melting point, hygroscopicity, compressibility, and density, providing an effective way to improve the performance of cosmetic ingredients. Currently, cocrystallization technology is widely used in the cosmetics and health product industries. However, there are currently no known combinations of supramolecular compounds related to betaine-glycyrrhizin cocrystallization on the market. Therefore, this paper proposes a glycyrrhizin-betaine cocrystallization method, its preparation, and its applications. Summary of the Invention

[0005] The present invention aims to at least solve one of the technical problems existing in the prior art. Therefore, one object of the present invention is to provide a glycyrrhizin-betaine eutectic, its preparation method, and its uses.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A glycyrrhizin-betaine eutectic, comprising betaine and glycyrrhizin molecules, wherein the molecular formula of the glycyrrhizin-betaine eutectic is C2. 45 H 51 NO 10 The molar ratio of betaine to glycyrrhizin is 1:2;

[0008] The X-ray powder diffraction pattern of the betaine-glycyrrhizin eutectic exhibits characteristic peaks at at least the following 2θ angles: 4.0°±0.2°, 8.0°±0.2°, 12.0°±0.2°, 15.5°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 18.7°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 24.1°±0.2°, and 24.7°±0.2°.

[0009] As a further optimization of the present invention, the eutectic is a monoclinic crystal system, space group P21, with the following cell parameters: α=90°, β=92.30(3)°, γ=90°,

[0010] As a further optimization of the present invention, the differential scanning calorimetry spectrum of the eutectic has a characteristic endothermic peak near 236.3±2℃.

[0011] As a further optimization of the present invention, the infrared spectrum of the eutectic is at 3467.37 cm⁻¹. -1 ±2cm -1 2975.92cm -1 ±2cm -1 1634.76cm -1 ±2cm -1 1524.75cm -1 ±2cm -1 1329.82cm -1 ±2cm -1 1374.91cm -1 ±2cm -1 1213.10cm -1 ±2cm -1 1087.61cm -1 ±2cm -1 1173.41cm -1 ±2cm -1 1114.72cm -1 ±2cm -1 1155.40cm -1 ±2cm -1 1288.22cm -1 ±2cm -1 803.49cm -1 ±2cm -1 772.03cm -1 ±2cm -1 717.46cm -1 ±2cm -1981.63cm -1 ±2cm -1 837.53cm -1 ±2cm -1 632.81cm -1 ±2cm -1 531.24cm -1 ±2cm -1 486.91cm -1 ±2cm -1 It has a characteristic peak;

[0012] In particular, the infrared spectrum of the eutectic is also at 1400.69 cm⁻¹. -1 ±2cm -1 1477.75cm -1 ±2cm -1 1329.82cm -1 ±2cm -1 1052.65cm -1 ±2cm -1 1433.05cm -1 ±2cm -1 1359.85cm -1 ±2cm -1 1583.81cm -1 ±2cm -1 1009.33cm -1 ±2cm -1 933.32cm -1 ±2cm -1 849.62cm -1 ±2cm -1 898.44cm -1 ±2cm -1 1052.65cm -1 ±2cm -1 It has a characteristic peak.

[0013] A method for preparing glycyrrhizin-betaine eutectic, applied to the glycyrrhizin-betaine eutectic, wherein the method is selected from one of the following two methods:

[0014] Method 1: Solid-state synthesis method

[0015] Weigh approximately 50 mg of glycyrrhiza glabra into a sample vial and add the corresponding solvent to suspend the sample. Then add 0.5-1 eq. of betaine and stir overnight at room temperature. If no solid precipitates, precipitate the solid by volatilization crystallization or by dissolution crystallization. Collect the solid by centrifugation for XRPD testing.

[0016] Method 2: Wet grinding method

[0017] Weigh out a certain amount of glycyrrhizin and betaine, mix them together, then add 200 μL of the corresponding solvent, grind the solids together in a mortar, and then collect the powder for PXRD testing.

[0018] As a further optimization of the present invention, in method two, the stoichiometric ratio of glycyrrhizin to betaine is 2:1.

[0019] As a further optimization of the present invention, in method one, the solvent is one or more of methanol, ethanol, ethyl acetate, and acetone / water mixed solvent;

[0020] In Method 2, the solvent is one or more of methanol, ethanol, acetonitrile, ethyl acetate, and acetone / water mixed solvent.

[0021] Uses of glycyrrhizin-betaine eutectic in the preparation of cosmetics, health products, food, pharmaceuticals, pharmaceutical excipients and feed.

[0022] Compared with the prior art, the beneficial effects of the present invention are:

[0023] This invention proposes a novel cocrystal supramolecular compound—glabridin-betaine cocrystal—which is formed by the interaction of betaine and glabridin molecules through hydrogen bonds. This cocrystal exhibits neutral properties, is mild and non-irritating, and is suitable as an active ingredient in cosmetics or health products.

[0024] Compared to glycyrrhizin monomer, the glycyrrhizin-betaine eutectic of this invention exhibits higher chemical purity and better chemical stability. Compared to betaine monomer, the glycyrrhizin-betaine eutectic of this invention demonstrates superior solid-state stability. Betaine monomer deliquesces within 5 days under high humidity (25°C & 90% RH) and accelerated conditions (40°C & 75% RH), affecting product storage and transportation. In contrast, the eutectic of this invention remains stable for 30 days under the same conditions, significantly improving the product's storage and transportation resistance. Attached Figure Description

[0025] Figure 1 This is one of the characterization results of the glycyrrhizin-betaine eutectic of the present invention;

[0026] Figure 2 The second figure shows the characterization results of the glycyrrhizin-betaine eutectic of the present invention.

[0027] Figure 3 Figure 3 shows the characterization results of the glycyrrhizin-betaine eutectic of the present invention.

[0028] Figure 4Figure 4 shows the characterization results of the glycyrrhizin-betaine eutectic of the present invention.

[0029] Figure 5 This is a single-crystal structure diagram of the glycyrrhizin-betaine of the present invention;

[0030] Figure 6 This is a comparison of magnified and small-scale experiments showing the formation of a eutectic of glycyrrhizin and betaine in this invention.

[0031] Figure 7 This is one of the results of the stability test of the glycyrrhizin-betaine eutectic of the present invention;

[0032] Figure 8 Figure 2 shows the results of the stability test of the glycyrrhizin-betaine eutectic of the present invention;

[0033] Figure 9 Figure 3 shows the results of the stability test of the glycyrrhizin-betaine eutectic of the present invention;

[0034] Figure 10 Figure 4 shows the results of the stability test of the glycyrrhizin-betaine eutectic of the present invention;

[0035] Figure 11 Figure 5 shows the results of the stability test of the glycyrrhizin-betaine eutectic of the present invention. Detailed Implementation

[0036] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0037] A glycyrrhizin-betaine eutectic, comprising betaine and glycyrrhizin molecules, wherein the molecular formula of the glycyrrhizin-betaine eutectic is C2. 45 H 51 NO 10 The molar ratio of betaine to glycyrrhizin is 1:2.

[0038] Sample testing conditions:

[0039] (1)XRPD

[0040] Testing instrument: Rigaku SmartLab SE

[0041] Detection conditions: X-ray tube voltage 40 Ω, X-ray tube current 40 mA, scanning range 3-40° (2θ), step size 0.02°, scan speed 5° / min.

[0042] Testing basis: Appendix IX, X-ray powder diffraction method, People's Republic of China (2010 Edition, Part II).

[0043] (2) TGA

[0044] Testing instrument: Netzsch STA 449F3

[0045] Detection conditions: Nitrogen gas, 50 mL / min

[0046] Scanning program: 30-400℃, heating rate: 10℃ / min

[0047] Sample weight: 5 mg (alumina sample dish)

[0048] Testing standard: JY / T 014-1996 General Rules for Thermal Analysis

[0049] (3) DSC

[0050] Testing instrument: Netzsch STA 449F3

[0051] Detection conditions: Nitrogen gas, 50 mL / min

[0052] Scanning program: 30-400℃, heating rate: 10℃ / min

[0053] Sample weight tested: 3 mg (alumina sample dish)

[0054] Testing standard: JY / T 014-1996 General Rules for Thermal Analysis

[0055] (4) Micro ED

[0056] Testing instrument: JEOL 2100PLUS

[0057] Detection conditions: Ambient temperature 100K, accelerating voltage 200kV, wavelength

[0058] (5) Infrared spectroscopy

[0059] Testing instrument: PE Fourier transform infrared microscope system (Spotlight 200i)

[0060] Detection conditions: Potassium bromide tablet method

[0061] Testing standard: GB / T 6040-2002 General Rules for Infrared Spectroscopic Analysis

[0062] The technical solution provided by this invention:

[0063] Example 1

[0064] Weigh 50 mg of glycyrrhizin into a sample bottle and add 1 mL of methanol to suspend it. Add 1 eq. of betaine and clarify. Then stir overnight at room temperature to volatilize the solid and perform XRPD test to obtain glycyrrhizin-betaine eutectic.

[0065] The DSC / TGA spectrum, IR spectrum, PXRD spectrum, NMR spectrum, and single crystal structure diagram of the eutectic are as follows: Figures 1-5 As shown. Crystal structure data are shown in Tables 1-7.

[0066]

[0067] Table 1 Crystallographic parameters and structural refinement parameters

[0068]

[0069]

[0070]

[0071] Table 2 Atomic coordinates and isotropic parameters

[0072]

[0073]

[0074] Table 3 Bond Lengths

[0075]

[0076]

[0077] Table 4 Bond Angles

[0078]

[0079] Table 5 Hydrogen Bonds

[0080]

[0081]

[0082]

[0083] Table 6 Angle of Torsion

[0084]

[0085]

[0086]

[0087] Table 7 Hydrogen Atom Coordinates

[0088] Example 2

[0089] Weigh 50 mg of glycyrrhizin into a sample bottle and add 1 mL of ethanol to suspend it. After adding 1 eq. of betaine, it still thickened. Then, stir overnight at room temperature. The solid was collected by centrifugation and XRPD test to obtain glycyrrhizin-betaine eutectic.

[0090] Example 3

[0091] Weigh 50 mg of glycyrrhizin into a sample vial and add 1 mL of ethyl acetate to suspend it. After adding 1 eq. of betaine, it still thickened. Then, stir overnight at room temperature. The solid was collected by centrifugation and XRPD test to obtain glycyrrhizin-betaine eutectic (with a small amount of betaine).

[0092] Example 4

[0093] Weigh 50 mg of glycyrrhizin into a sample vial and add 1 mL of acetone / water mixed solvent to suspend it. Add 1 eq. of betaine and clarify. Then, stir overnight at room temperature to volatilize the solid and perform XRPD test to obtain glycyrrhizin-betaine eutectic.

[0094] Example 5

[0095] Weigh 50 mg of glycyrrhizin into a sample vial and add 1 mL of methanol to suspend it. After adding 0.5 eq. of betaine, clarify the solution and then stir it overnight at room temperature. The solid was volatilized and XRPD test was performed to obtain glycyrrhizin-betaine eutectic.

[0096] Example 6

[0097] Weigh 50 mg of glycyrrhizin into a sample vial and add 1 mL of ethanol to suspend it. After adding 0.5 eq. of betaine, it still thickened. Then, stir overnight at room temperature. The solid was collected by centrifugation and XRPD test was performed to obtain glycyrrhizin-betaine eutectic.

[0098] Example 7

[0099] Weigh 50 mg of glycyrrhizin into a sample bottle and add 1 mL of ethyl acetate to suspend it. After adding 0.5 eq. of betaine, it still thickened. Then, stir overnight at room temperature. The solid was collected by centrifugation and XRPD test was performed to obtain glycyrrhizin-betaine eutectic.

[0100] Example 8

[0101] Weigh 50 mg of glycyrrhizin into a sample vial and add 1 mL of acetone / water mixed solvent to suspend it. After adding 0.5 eq. of betaine, clarify the solution and then stir it overnight at room temperature. The solid was volatilized and XRPD test was performed to obtain glycyrrhizin-betaine eutectic.

[0102] Example 9

[0103] Weigh 50 mg of glycyrrhizin, add 200 μL of methanol, and grind with 0.5 eq of betaine in a mortar. Then collect the powder and perform PXRD test to obtain glycyrrhizin-betaine eutectic.

[0104] Example 10

[0105] Weigh 50 mg of glycyrrhizin, add 200 μL of ethanol, and grind with 0.5 eq of betaine in a mortar. Then collect the powder and perform PXRD test to obtain glycyrrhizin-betaine eutectic.

[0106] Example 11

[0107] Weigh 50 mg of glycyrrhizin, add 200 μL of acetonitrile, and grind with 0.5 eq of betaine in a mortar. Then collect the powder and perform PXRD test to obtain glycyrrhizin-betaine eutectic.

[0108] Example 12

[0109] Weigh 50 mg of glycyrrhizin, add 200 μL of ethyl acetate and grind in a mortar, then grind with 0.5 eq of betaine in a mortar. Collect the powder and perform PXRD test to obtain glycyrrhizin-betaine eutectic.

[0110] Example 13

[0111] Weigh 50 mg of glycyrrhizin and betaine, add 200 μL of acetone / water mixed solvent, and grind with 0.5 eq of betaine in a mortar. Then collect the powder and perform PXRD test to obtain glycyrrhizin-betaine eutectic.

[0112] Example 14

[0113] To prepare a scaled-up eutectic of glycyrrhizin and betaine, 1 g of glycyrrhizin was weighed into a sample vial and suspended in 10 mL of ethanol. Then, 0.5 eq. of betaine was added, and the suspension was maintained. The mixture was stirred overnight at room temperature. The solid was collected by vacuum filtration and subjected to XRPD analysis to obtain the glycyrrhizin-betaine eutectic.

[0114] In this embodiment, a comparison is made between the glycyrrhizin-betaine eutectic formation-scale test (ZY-24-1 batch) and the small-scale test (ZY-23-1 batch). Figure 6 As shown.

[0115] Experimental Example 15

[0116] Physical stability test of glycyrrhizin-betaine cocrystal: ~30 mg of the cocrystal sample prepared in Example 14 and betaine monomer were placed in environments of 60℃ (closed), 25℃ & 90%RH (open), light irradiation (5000Lux±500Lux; closed), and accelerated conditions of 40℃ & 75%RH (open) for 5 days, 10 days, 20 days, and 30 days, respectively, and XRPD was performed. The test results are shown in Table 9. Figure 7 As shown:

[0117]

[0118]

[0119] Table 9

[0120] As shown in Table 9, the glycyrrhizin-betaine eutectic exhibited no significant change in crystal form and maintained stable physical properties after 5, 10, 20, and 30 days under various conditions, including 60℃ (closed), 25℃ & 90%RH (open), light irradiation (5000Lux±500Lux; closed), and accelerated conditions at 40℃ & 75%RH (open). The betaine monomer samples deliquesced after 5 days under both 25℃ & 90%RH (open) and accelerated conditions at 40℃ & 75%RH (open). This indicates that the glycyrrhizin-betaine eutectic of this invention exhibits superior solid-state stability compared to the betaine monomer.

[0121] Experimental Example Sixteen

[0122] Chemical stability test of glycyrrhizin-betaine eutectic: ~30 mg of the eutectic sample prepared in Example 14 was placed in environments of 60℃ (closed), 25℃ & 90%RH (open), light irradiation (5000Lux±500Lux; closed), and accelerated conditions of 40℃ & 75%RH (open) for 5, 10, 20, and 30 days, respectively, and analyzed by HPLC. The test results are as follows. Figures 8-11 As shown.

[0123] The purity of the eutectic was determined by high performance liquid chromatography (HPLC). Chromatographic conditions: column: C18, 4.6 x 250 mm (5 μm), mobile phase: potassium dihydrogen phosphate-acetonitrile-methanol (0-2 min, 90:5:5; 6 min, 35:10:55; 10 min, 35:20:45; 12 min, 35:55:10; 20 min, 35:55:10; 25 min, 95:5:5), detection wavelength: 230 nm, flow rate: 1.0 mL / min －1The column temperature was 35℃, and the injection volume was 5 μL. The test results are shown in Table 10:

[0124]

[0125]

[0126] Table 10

[0127] As shown in Table 10, the glycyrrhizin-betaine eutectic of this invention exhibits higher chemical purity compared to the glycyrrhizin monomer. Furthermore, the eutectic samples were placed in environments of 60℃ (closed), 25℃ & 90% RH (open), light irradiation (5000 Lux ± 500 Lux; closed), and accelerated conditions at 40℃ & 75% RH (open) for 30 days, respectively, and the purity of the samples did not change significantly, indicating that the eutectic possesses good chemical stability.

[0128] Example 17

[0129] The transdermal permeation test was performed on the eutectic sample of glycyrrhizin monomer and Example 15, as follows:

[0130] Step 1: Add water to the receiving cell and preheat it (the sample solubility needs to meet the leakage conditions during the experiment, and the temperature should be 37±1℃).

[0131] Step 2: Secure the appropriately sized pigskin between the supply pool and the receiving pool;

[0132] Step 3: Replenish the receiving tank liquid, remove air bubbles, and place it in the diffusion tank for stirring;

[0133] Step 4: Add the sample to be tested to the supply tank;

[0134] Step 5: Take samples at regular intervals, collect / replenish the solution (1-6 hours), and then perform HPLC testing on the filtrate.

[0135] The test results are shown in Table 11:

[0136]

[0137]

[0138] Table 11

[0139] Example 18

[0140] Biological solubility test: A certain mass of glycyrrhizin monomer and the cocrystal sample of Example 15 were weighed into sample bottles, and then 1-2 mL of water was added to form suspensions. All suspensions were shaken at 200 rpm at 37°C, and samples were taken at 0.5 h, 2 h, 6 h, and 24 h. The filtrates were then analyzed by HPLC. The test results are shown in Table 12:

[0141]

[0142] Table 12

[0143] As shown in Table 12, the solubility of the eutectic in aqueous solvents is improved compared to the glycyrrhizin monomer, although the improvement is not significant. This helps the eutectic raw material to be more uniformly dispersed in aqueous solvents during application, thereby improving its bioavailability on human skin and enhancing its efficacy.

[0144] All parts not described in this invention are the same as or can be implemented using existing technology. Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A glabridin-betaine cocrystal, characterized in that: The cocrystal includes betaine and glabridin molecules. The molecular formula of glabridin-betaine cocrystal is C 45 H 51 NO 10 , the molar ratio of betaine to glabridin is 1:2; The X-ray powder diffraction pattern of the glabridin-betaine cocrystal has characteristic peaks at least at 2θ angles of 4.0°±0.2°, 8.0°±0.2°, 12.0°±0.2°, 15.5°±0.2°, 16.0°±0.2°, 17.5°±0.2°, 18.0°±0.2°, 18.7°±0.2°, 21.0°±0.2°, 22.2°±0.2°, 24.1°±0.2°, and 24.7°±0.2°.

2. The glabridin-betaine cocrystal according to claim 1, characterized in that: The eutectic is monoclinic, P21 space group, unit cell parameters: α=90°, β=92.30(3)°, γ=90°, 3. The glabridin-betaine cocrystal according to claim 1, characterized in that: The differential scanning calorimetry analysis spectrum of the co-crystal has a characteristic endothermic peak near 236.3±2°C.

4. The glabridin-betaine cocrystal according to claim 1, characterized in that: The infrared analysis spectrum of the co-crystal is at 3467.37 cm -1 ±2cm -1 、2975.92cm -1 ±2cm -1 、1634.76cm -1 ±2cm -1 、1524.75cm -1 ±2cm -1 、1329.82cm -1 ±2cm -1 、1374.91cm -1 ±2cm -1 、1213.10cm -1 ±2cm -1 、1087.61cm -1 ±2cm -1 、1173.41cm -1 ±2cm -1 、1114.72cm -1 ±2cm -1 、1155.40cm -1 ±2cm -1 、1288.22cm -1 ±2cm -1 、803.49cm -1 ±2cm -1 、772.03cm -1 ±2cm -1 、717.46cm -1 ±2cm -1 、981.63cm -1 ±2cm -1 、837.53cm -1 ±2cm -1 、632.81cm -1 ±2cm -1 、531.24cm -1 ±2cm -1 、486.91cm -1 ±2cm -1 There are characteristic peaks at In particular, the infrared analysis spectrum of the cocrystal is also at 1400.69 cm -1 ±2cm -1 、1477.75cm -1 ±2cm -1 、1329.82cm -1 ±2cm -1 、1052.65cm -1 ±2cm -1 、1433.05cm -1 ±2cm -1 、1359.85cm -1 ±2cm -1 、1583.81cm -1 ±2cm -1 、1009.33cm -1 ±2cm -1 、933.32cm -1 ±2cm -1 、849.62cm -1 ±2cm -1 、898.44cm -1 ±2cm -1 、1052.65cm -1 ±2cm -1 There are characteristic peaks.

5. A method for preparing glabridin-betaine co-crystal, applied to the glabridin-betaine co-crystal according to any one of claims 1 to 4, characterized in that: The method is selected from one of the following two methods: Method 1: Solid-state synthesis method: Weigh 50 mg of glabridin into a sample bottle and add the corresponding solvent to make them all in a suspended state, then add 0.5-1 eq. of betaine, stir overnight at room temperature, if no solid is precipitated, precipitate the solid by evaporation crystallization or dissolution crystallization, collect the solid by centrifugation or filtration for XRPD test; Method 2: Wet grinding method: Weigh some glabridin and betaine and mix them, then add 200 μL of the corresponding solvent, grind them with the solid in a mortar, and then collect the powder for PXRD test.

6. The method for preparing the glabridin-betaine cocrystal according to claim 5, characterized in that: In method 2, the stoichiometric ratio of glabridin to betaine is 2:

1.

7. The method for preparing the glabridin-betaine cocrystal according to claim 5, characterized in that: In method 1, the solvent is one or more of methanol, ethanol, ethyl acetate, and acetone / water mixed solvent; In method 2, the solvent is one or more of methanol, ethanol, acetonitrile, ethyl acetate, and an acetone / water mixed solvent.

8. Use of the glabridin-betaine co-crystal according to any one of claims 1 to 4 in the preparation of cosmetics, health products, foods, medicines, pharmaceutical excipients and feeds.

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