STORAGE STABLE MIXTURES, METHOD OF IMPROVING RETENTION OF A COMPOUND AND USE OF RICE HULLS AND/OR RICE BRAN TO ENHANCE RETENTION OF A COMPOUND

Abstract

The present invention relates to improved formulations of propandiol mononitrate and derivatives thereof as well as to the production of such formulations.

Claims

1. A storage stable mixture, comprising (1) a compound of formula (I) ##STR00006## wherein n is an integer from 1 to 15 R.sup.1 is selected from the group consisting of H, C.sub.1-C.sub.6alkyl, phenyl, —OH, —NH.sub.2, —CN, —COOH, —O(C═O)R.sup.8, —NHC(═O)R.sup.8, SO.sub.2NHR.sup.8, and —ONO.sub.2, and R.sup.8 is C.sub.1-C.sub.6alkyl, phenyl, pyridyl such as preferably 2-pyridyl with the proviso that when n is >3 the hydrocarbon chain may be interrupted by —O— or —NH—, and (2) rice hulls and/or rice bran.

2. The storage stable mixture according to claim 1, wherein the ratio (w/w) of the rice hulls and/or the rice bran to the compound of formula (I) is at least 1, preferably at least 5, more preferably at least 10, most preferably at least 25.

3. The storage stable mixture according to claim 1, comprising (b1) a liquid formulation comprising (i) a compound of formula (I) and (ii) an edible solvent, preferably propylene glycol or water, and (b2) rice hulls and/or rice bran.

4. The storage stable mixture according to claim 1, comprising (a1) a powderous formulation comprising (i) the compound of formula (I) and (ii) silica, and (a2) rice hulls and/or rice bran.

5. The storage stable mixture according to claim 1, wherein the compound according to formula (I) is 1,3-propandiol mononitrate.

6. The storage stable mixture according to claim 4, wherein the weight ratio of the rice hulls and/or rice bran to the powderous formulation is selected in the range of 50:1 to 1:5, preferably in the range of 40:1 to 1:2, most preferably in the range of 30:1 to 1:1 or 20:1 to 1:1.

7. The storage stable mixture according to claim 4, wherein the powderous formulation consists essentially of (i) 2 to 20 wt-%, based on the total weight of the powderous formulation, of a compound of formula (I), and (ii) at least 25 wt-%, based on the total weight of the powderous formulation, of silica, and (iii) 10 wt-% to 45 wt-%, based on the total weight of the powderous formulation, of an edible oil, and (iv) 0 to 10 wt-%, based on the total weight of the powderous formulation, of an additive.

8. The storage stable mixture according to claim 7, wherein the edible oil in the powderous formulation is selected from the group consisting of propyleneglycol, canola oil, corn oil, rapeseed oil, sunflower oil, middle chain triglyceride (MCT), water and glycerol as well as mixtures thereof, preferably propylene glycol or water.

9. The storage stable mixture according to claim 4, wherein the powderous formulation consists essentially of (i) 2 to 15 wt-%, based on the total weight of the powderous formulation, of propandiol mononitrate, and (ii) at least 45 wt-%, based on the total weight of the powderous formulation, of silica, and (iii) 20 to 40 wt-%, based on the total weight of the powderous formulation, of propyleneglycol.

10. The storage mixture according to claim 3, wherein the mixture is a premix consisting essentially of (b1) and (b2) respectively of (a1) and (a2).

11. The storage mixture according to claim 4, wherein the mixture is a premix further comprising (a3) active ingredient selected from the group of water-soluble and/or fat-soluble vitamins, trace and/or macro minerals, amino acids as well as mixtures thereof, and optionally (a4) edible oil, with the proviso that the amount of ingredients (a1) to (a4) sum up to 100 wt.-%.

12. The storage mixture according to claim 4, wherein the mixture is a feed product further comprising (a3/1) active ingredient selected from the group consisting of water-soluble and/or fat-soluble vitamins, trace and/or macro minerals, amino acids as well as mixtures thereof and (a3/2) feed ingredient selected from the group of roughage and concentrates, and optionally (a4) edible oil.

13. Use of a rice hulls and/or rice bran to enhance the retention of a compound of formula (I) ##STR00007## wherein n is an integer from 3 to 9 R.sup.1 is selected from the group consisting of —OH, —COOH and —ONO.sub.2 with the proviso that when n is >3 the hydrocarbon chain may be interrupted by —O— or —NH—, with the proviso that the ratio (w/w) of the rice hulls and/or the rice bran to the compound of formula (I) is at least 1, preferably at least 5, more preferably at least 10, most preferably at least 25.

14. A method of improving the retention of a compound of formula (I) ##STR00008## wherein n is an integer from 3 to 9 R.sup.1 is selected from the group consisting of —OH, —COOH and —ONO.sub.2 with the proviso that when n is >3 the hydrocarbon chain may be interrupted by —O— or —NH—, said method comprising admixing the compound of formula (I) with rice hulls and/or rice bran with the proviso that the ratio (w/w) of the rice hulls and/or the rice bran to the compound of formula (I) is at least 1, preferably at least 5, more preferably at least 10, most preferably at least 25.

15. Use according to claim 14, wherein the retention after at least 4 weeks is at least 80%, preferably at least 85% most preferably at least 90% such as in particular at least 95%.

Description

EXAMPLES

General Information

[0177] A.) HPLC Method

[0178] Agilent High Performance Liquid Chromatography 1260 Infinity system, using an Aquasil C18, 150×3 mm, 3 μm column and detecting at 210 nm. The column oven was set to 23° C., the autosampler not temperature controlled. The mobile phase consisted of mobile phase A (940 mL Milli-Q-water+60 ml acetonitrile+1 mL methane sulfonic acid) and mobile phase B (800 ml Milli-Q-water+200 ml acetonitrile+1 mL methane sulfonic acid) which were used in gradient mode (0 min: 0% B, 15 min: 0% B, 15.5 min: 100% B, 21 min: 100% B, 21.5 min: 0% B, 25 min: 0% B (=end of run)) with a flow of 0.4 ml/min.

[0179] B.) Powderous Formulation Comprising Propandiol Mononitrate (PF-PDMN)

[0180] To 80 g of silica (Newsil C50) placed on a beaker, are added 80 g of a 20 wt.-% propandiol mononitrate (PDMN) solution in propyleneglycol under gentle agitation at room temperature. After 5 minutes agitation, the adsorption is completed and a free-flowing powder is obtained.

[0181] C.) Liquid formulation comprising propandiol mononitrate in propyleneglycol (PG-PDMN) 20 g of propandiol mononitrate and 80 g of propyleneglycol are mixed under gentle agitation until a clear solution is obtained.

Example 1: Retention of PDMN in PF-PDMN Admixed with Different Organic Carriers

[0182] 10 g of PF-PDMN and 90 g of an organic carrier as outlined in table 1 have been mixed with a TURBULA® Shaker-Mixer (64 rotations/min) for 10 min, sieved through a 2 mm sieve and mixed again for 10 min to obtain homogenous mixtures (100 g batches). Then 10 g of the respective mixtures were stored in reclosed PE bags at 25° C. under controlled atmosphere (50% r.H) for 1 month. Afterwards the remaining content of PDMN was determined by HPLC. The results (as relative concentration to the initial value set to 100%) are presented Table 1.

TABLE-US-00001 TABLE 1 Retention of PDMN in PF-PDMN in dependence of various organic carriers # Organic carrier Retention [%] Inv 1 Rice Hulls 89 Ref 1 Modified starch* 48 *starch sodium octenyl succinate (“OSA-starch”).

[0183] As can be retrieved from table 1, the use of the rice hulls according to the present invention resulted in an improved retention of the active compared to other organic carriers commonly used in the feed industry.

Example 2: Retention of PDMN in a Premix Comprising Different Carriers

[0184] In a comparative trial, 80 g of a mineral premix consisting of vitamins (Rovimix AD3 1000/200 (0.1 wt.-%) & Rovimix E 50 Ads (1 wt.-%)), minerals (92.9 wt.-%) and PF-PDMN (6 wt.-%) was admixed with 20 g of either rice bran or diatomaceous earth (Kieselgur) and then stored for 3 months in reclosed PE bags at 25° C. under controlled atmosphere (50% r.H). Afterwards the remaining content of PDMN was determined by HPLC. The results (as relative concentration to the initial value set to 100%) are presented Table 2.

TABLE-US-00002 TABLE 2 Retention of PDMN in a premix comprising different carriers # Mineral premix Inorganic carrier Retention Inv 2 80 wt.-% Rice bran 20 wt.-% 71% Ref 2 80 wt.-% Diatomaceous earth 66% (Kieselgur) 20 wt.-%

[0185] As can be seen the addition of rice bran to the mineral premix containing PF-PDMN results in a significantly better retention of PDMN compared to another carrier commonly used in the feed industry.

Example 3: Retention of PDMN in PF-PDMN Admixed with Rice Hulls in Different Ratios

[0186] PF-PDMN and rice hulls in the weight-ratios as outlined in table 3 have been mixed with a TURBULA® Shaker-Mixer (64 rotations/min) for 10 min, sieved through a 2 mm sieve and mixed again for 10 min to obtain homogenous mixtures (50 g batches). Then two samples (5 g each) were stored in reclosed PE bags at 25° C. under controlled atmosphere (60% r.H) for 2 months. Afterwards the remaining content of PDMN was determined by HPLC. The results (as relative concentration to the initial value set to 100%) are presented Table 3.

TABLE-US-00003 TABLE 3 Retention of PDMN in PF-PDMN admixed with rice hulls in different ratios # Ratio [%] Retention [%] Inv 3 90/10 98 Inv 4 50/50 92 Inv-5 30/70 98

[0187] As can be retrieved from table 3, the use of the rice hulls according to the present invention resulted in an improved retention of the active over a broad concentration range.

Example 4: Retention of PDMN in PG-PDMN Admixed with Rice Hulls in Different Ratios

[0188] Rice hulls were weighted into a PE bag. Then the corresponding amount of a solution of 20 wt.-% of PDMN in propyleneglycol (as outlined in table 4) was sprayed into the bag with a compressed air gun at 0.5 bar pressure (50 g batches). Afterwards the bag was closed and mixed manually. Then the rice hull/PG-PDMN mixture was transferred into a 400 ml flask and mixed with a TURBULA® Shaker-Mixer (64 rotations/min) for 10 min to obtain a homogeneous mixture. Then two samples (5 g each) of the respective mixtures were stored in reclosed PE bags at 25° C. under controlled atmosphere (60% r.H) for 2 months. Afterwards the remaining content of PDMN was determined by HPLC. The results (as relative concentration to the initial value set to 100%) are presented Table 4.

TABLE-US-00004 TABLE 4 Retention of PDMN in PG-PDMN admixed with rice hulls in different ratios # Ratio [%] Retention [%] Inv 6 10/90 92 Inv 7 30/70 93 Inv-8 50/50 93

[0189] As can be retrieved from table 4, the use of the rice hulls according to the present invention resulted also in a significant improvement of the retention in the absence of a silica carrier over a broad concentration range.