Process for the preparation of high water affinity type products with controlled humidity

Abstract

The invention relates to a new process for the preparation of high water affinity type products with controlled humidity via spray drying in a suitable spray drying equipment applying specific spray drying parameters:

Claims

1. A process for the preparation of high water affinity type products with controlled humidity, characterized in that an aqueous solution of the high water affinity type product is spray dried in a suitable spray drying equipment applying the following spray drying parameters: TABLE-US-00010 Inlet N.sub.2 temperature (° C.) 150 to 300 Outlet N.sub.2 temperature (° C.)  50 to 150 thereby controlling the water content of the spray dried high water affinity type product in a range of 1% w/w to 20% w/w.

2. The process of claim 1, wherein the spray drying parameters are: TABLE-US-00011 High water affinity type product  1 to 50 concentration in the feed solution (% w/w) Inlet N.sub.2 temperature (° C.) 180 to 220 Outlet N.sub.2 temperature (° C.)  70 to 100

3. The process of claim 1 wherein the spray drying parameters are: TABLE-US-00012 High water affinity type product  5 to 25 concentration in the feed solution (% w/w) Inlet N.sub.2 temperature (° C.) 180 to 220 Outlet N.sub.2 temperature (° C.)  70 to 100

4. The process of claim 1, wherein the ratio Gas Rate Drying to Feed Rate is between 1 and 200, preferably between 10 and 150.

5. The process of claim 1, wherein the ratio Gas Rate Nozzle to Feed Rate is between 0.5 and 10, preferably 1 and 8.

6. The process of claim 1, wherein the suitable spray drying equipment comprises a spray chamber and an atomizer selected from a pressure drop- or a two fluid nozzle or from a rotary atomizer.

7. The process of claim 1, wherein the suitable spray drying equipment comprises a spray chamber and an atomizer selected from a two fluid nozzle.

8. The process of claim 1, wherein the following additional spray drying parameters are applied: TABLE-US-00013 Gas rate drying (kg/h) 10 to 50 Gas rate nozzle (kg/h) 0.5 to 3  

9. The process of claim 8, wherein the spray drying parameters are applied: TABLE-US-00014 Gas rate drying (kg/h) 15 to 25 Gas rate nozzle (kg/h) 0.8 to 1.5

10. The process of claim 1, wherein the residual water content of the spray dried high water affinity type product is in the a range of 5% w/w to 15% w/w, more preferably in the a range of 10% w/w to 15% w/w.

11. The process of claim 1, wherein the bulk density of the spray dried oligonucleotide is in the a range of 0.1 g/ml to 0.5 g/ml, preferably in the a range of 0.3 g/ml to 0.5 g/ml.

12. The process of claim 1, wherein the high water affinity type product is an oligonucleotide.

13. The process of claim 12, wherein the oligonucleotide consists of optionally modified DNA, RNA or LNA nucleoside monomers or combinations thereof and is 10 to 40, preferably 10 to 25 nucleotides in length.

14. A high water affinity type product, obtainable by the spry drying process as defined in claim 1.

15. The high water affinity type product of claim 14, wherein the high water affinity type product is an oligonucleotide and the residual water content is in the a range of 1% w/w to 20% w/w, preferably is in the a range of 5% w/w to 15% w/w, more preferably in the a range of 10% w/w to 15% w/w.

Description

EXAMPLES

[0091] Preparation of GN2-AM-C6-5′-caG*.sup.MeC*G*t*a*a*a*g*a*g*a*G*G-3′ (SEQ ID NO: 1)

[0092] The title product has been prepared in accordance with Example 3B and purified in accordance with Example 4B1 of the International Patent Publication WO 2018/215391.

Example 1

[0093] Spray Drying of GN2-AM-C6-5′-caG*.sup.MeC*G*t*a*a*a*g*a*g*a*G*G-3′ (SEQ ID NO: 1)

[0094] 13 g of the title oligonucleotide were dissolved in 117 g water at room temperature. This solution was fed into a Niro SDMICRO™ (GEA Process Engineering A/S, Soeborg Denmark) through a co-current two-fluid nozzle (Ø0.5 mm, temperature 50° C., nitrogen atomizing flow rate 0.8 kg/h). The feed was atomized into a stream of hot nitrogen (Inlet temperature 220° C.) at a liquid feed rate of 10 g/min and a nitrogen flow rate of 15 kg/h. An outlet temperature of ca. 70° C. was obtained. The generated solid were separated from the gas flow by a cyclone connected to the drying chamber into a glass bottle: 11.4 g solids were collected with a residual water content of 12.3% w/w (isolated yield corrected for water content 90%) and a bulk density of 0.45 g/mL.

Examples 2 to 31

[0095] The following examples have been made in accordance with example 1, but with a variation of the key parameters.

TABLE-US-00007 Gas rate Gas rate Gas drying/ Gas nozzle/ Yield Solid rate Feed rate rate Feed rate Residual (water Example Conten T.sub.Inlet T.sub.Outlet drying ratio* nozzle ratio* Water corr.) Nr. % w/w ° C. ° C. kg/h — kg/h — % w/w % 2 10 210 100 20 48 1.0 2.4 7.48 31 3 5 210 100 20 42 1.0 2.1 6.84 23 4 5 220 100 20 37 1.5 2.8 4.97 63 5 15 210 90 20 37 1.0 1.9 6.77 71 6 20 210 90 20 39 1.0 2.0 7.63 67 7 20 210 90 20 39 0.8 1.6 6.49 89 8 20 190 80 20 30 1.0 1.5 9.25 75 9 20 190 70 20 35 1.0 1.8 11.14 63 10 20 180 70 20 35 1.0 1.8 8.60 70 11 20 190 70 18 30 1.0 1.7 11.01 63 12 20 200 70 18 27 1.0 1.5 10.65 63 13 20 210 70 18 35 1.0 2.0 11.23 63 14 17.5 200 85 20 28 1.0 1.4 8.67 62 15 25 180 70 25 23 1.2 1.1 9.59 63 16 10 220 70 25 104 1.2 5.0 12.19 60 17 10 180 85 15 21 0.8 1.1 7.73 60 18 10 180 70 25 119 0.8 3.8 10.37 52 19 10 220 100 15 21 1.2 1.7 5.42 47 20 25 220 100 25 139 1.2 6.7 7.43 67 21 25 180 88 15 38 1.2 3.1 5.91 60 22 25 180 70 15 31 0.8 1.7 10.80 65 23 17.5 200 85 20 32 1.0 1.6 5.60 76 24 10 220 100 25 76 0.8 2.4 7.16 74 25 10 180 100 25 83 1.2 4.0 5.70 60 26 25 180 100 25 42 0.8 1.3 5.76 55 27 25 220 70 15 38 1.2 3.1 14.50 52 28 10 180 70 15 14 1.2 1.1 9.93 61 29 25 220 70 25 83 0.8 2.7 13.31 45 30 25 220 100 15 25 0.8 1.3 5.84 98 31 17.5 200 85 20 39 1.0 2.0 8.12 72 *The Gas rate drying/Feed rate ratio and Gas rate nozzle/Feed rate ratio are dimension-less parameters independent from the size of the drying chamber and the atomizer.

[0096] Selected Bulk Densities:

TABLE-US-00008 Residual Water Bulk Density Example Nr. % w/w g/mL  1 12.28 0.45 14  8.67 0.40 16 12.19 0.25 28  9.93 0.40 30  5.84 0.40 31  8.12 0.30

Comparison Example

[0097] The title product has been prepared in accordance with Example 3B, purified in accordance with Example 4B land lyophilized in accordance with Example 4B2 of the International Patent Publication WO 2018/215391.

[0098] The material obtained is very hygroscopic, electrostatically charged, not free flowing and therefore difficult to manage.

[0099] The material was therefore conditioned in a climate chamber at 21° C. and 50% rel. humidity until the weight was constant, which was achieved after 48 h.

Examples 32 to 34

[0100] Examples 32 to 34 have been performed with the following to LNA's [0101] 5′-T*G*G*c*a*a*g*c*a*t*c*c*T*G*T*a-3′ (SEQ ID NO: 2) (Example 32 and 33) [0102] GN2-AM-C6-5′-caC*C*t*a*t*t*t*a*a*c*a*t*c*A*C*A*C-3′ (SEQ ID NO: 3) (Example 34)

[0103] in accordance with example 1.

TABLE-US-00009 Gas Gas Gas rate Gas rate Yield Solid rate drying/ rate nozzle/ Residual (Water Example Content T.sub.Inlet T.sub.Outlet drying Feed nozzle Feed Water corr.) Nr. % w/w ° C. ° C. kg/h rate kg/h rate % w/w % 32 10 210 112 5 4 1.0 1.0 4.60 58 33 5 210 112 5 4 1.0 1.0 5.20 65 34 5 210 110 5 4 1.5 1.0 3.20 34