Co-Crystal Former for indomethacin
2012.4.22
HSPiP Team Senior Developer, Dr. Hiroshi Yamamoto
I got very interesting paper about co-crystal formation.
International Journal of Pharmaceutics 407 (2011) 63–71
”Hansen solubility parameter as a tool to predict cocrystal formation”
They search the chemicals that reduce indomethacin co-crystal melting point with Hansen Solubility Parameters (HSP).
Because I am polymer chemist (or computational chemist), i do not know the difference of Eutectic and Co-crystal. What I understand from this paper are:
1. If the HSP of Co-Crystal Former(CCF) is near to indomethacin’s HSP, then it may form Co-Crystal.
2. The DSC analysis show that, “Eutectic melt onset temperature” become lower with similar HSP having CCFs.
I checked with HSPiP.
| Hcode | Name | T1 | T2 | dT(T1-T2) | Cocrystal |
| 20359 | indomethacin | ||||
| 22358 | 4,4-bipyridine | 111.5 | 96.3 | 15.2 | Yes |
| 22359 | 4-aminobenzamide; | 182.4 | 132.6 | 49.8 | No |
| 8965 | 4-aminobenzoic acid; | 187.7 | 133.7 | 54 | No |
| 9456 | 4-hydroxybenzoic acid; | 214.9 | 141.4 | 73.5 | No |
| 54 | benzoic acid; | 122.1 | 102.2 | 19.9 | No |
| 10808 | cinnamic acid; | 133.3 | 110.9 | 22.4 | Yes |
| 7123 | citric acid; | 155.2 | 149.8 | 5.4 | No |
| 22361 | cyclamic acid; | 179.3 | 152.5 | 26.8 | No |
| 7116 | glutaric acid; | 95.5 | 92.3 | 3.2 | No |
| 10415 | malic acid; | 130.2 | 102.7 | 27.5 | No |
| 8201 | malonic acid; MPdec | 134.5 | 128.1 | 6.4 | No |
| 22362 | neotame; | 75 | 72.1 | 2.9 | No |
| 8421 | nicotinamide; | 128.4 | 98.8 | 29.6 | Yes |
| 1156 | oxalic acid; MP dec | 189.5 | 139.3 | 50.2 | No |
| 1196 | saccharin; MP dec | 228 | 147.7 | 80.3 | Yes |
| 5157 | succinic acid; | 187.8 | 148.5 | 39.3 | No |
| 860 | urea; | 134.3 | 123.1 | 11.2 | No |
| 10819 | vanillic acid; | 209.3 | 144.6 | 64.7 | No |
T1: Cocrystal former onset melting temperature（℃）
T2: Eutectic melt onset temperature
In my database, some compounds have no melting point (decompose before melt), but DSC point of view, they have T1.
At first, let’s examine this T1.
The melting point of a solid is the temperature at which it changes state from solid to liquid. (Wiki)
So, vibration energy exceed molecular interaction energy then it start to melt. How can we evaluate molecular interaction energy? It’s depend on molecular shape or packing state and very difficult to estimate. The polymer chemists are accustom to cohesive energy when they think about Tg(Glass Transition Temperature) or viscosity of polymer. So it is natural connect Cohesive Energy to Melting Point.
Cohesive Energy = (dD^2+dP^2+dH^2)*Volume
I plot CCF’s Cohesive Energy to T1(melting point).
But I can not find the correlation.
So I analyzed with Multiple Regression (MR) Method.
melting point = 38.55*dD-2.55*dP+3.21*dH-617.77
This is much better. This scheme says that: dD(VDW force) play major role to melting point. VDW force is very adjacent force. The coefficient of dP is negative. dP is the force of polarity. I am not sure the reason but in crystal, polarity may work repulsive.
If I add Ovality term, the MR result become much better.
Then let’s examine T2:Eutectic melt onset temperature.
In the paper, they say “likes dissolve likes” and “likes make co-crystal” and “likes reduce T2”.
We use HSP distance when we evaluate this “likes”.
HSP distance＝sqrt(4*(dDtarget-dDsolvent)^2+(dPt-dPs)^2+(dHt-dHs)^2)
You can easily find out that shorter distance (<12) lead Co-Crystal “Yes”. So if you want to screening CCFs that co-Crystal “Yes”, HSP is the very powerful index.
Then I plot dT(=T1-T2) to HSP Distance, but I can not find good correlation.
So, again I made Multiple Regression(MR) scheme to predict dT. The important descriptors are same with T1 scheme. In the dT predict scheme HSP coefficients are become 26.8728*dD-1.7991*dP+1.4572*dH. dD and dH make increase dT and dP make decrease dT as same T1 scheme.
I checked Japanese Patents that claim CCFs. In JP2008-503495 include 89 CCF compounds and 62 compounds are in our database. I show the list below.(Hcode means Hansen Code)
| Hcode | CAS | Name | Melting Point |
| 54 | 65-85-0 | benzoic acid | 122 |
| 603 | 1592-23-0 | octadecanoic acid | 70 |
| 860 | 57-13-6 | Urea | Dec |
| 917 | 123-31-9 | p-hydroquinone | 170 |
| 1052 | 110-85-0 | piperazine | 106 |
| 1152 | 124-04-9 | adipic acid | 152 |
| 1156 | 144-62-7 | oxalic acid | 189Dec |
| 1163 | 50-81-7 | ascorbic acid | 190 |
| 1196 | 81-07-2 | Saccharin | 228 |
| 1200 | 58-08-2 | Caffeine | 238 |
| 1204 | 147-93-3 | salicylic acid | 159 |
| 1205 | 504-24-5 | 4-Aminopyridine | 158 |
| 1225 | 111-20-6 | sebacic acid | 134.5 |
| 1232 | 60-18-4 | l-Tyrosine | 342 |
| 1243 | 73-24-5 | Adenine | 220Sub |
| 5157 | 110-15-6 | succinic acid | 185 |
| 6094 | 147-71-7 | tartaric acid | 205 |
| 7024 | 79-14-1 | Glycolic Acid | 80 |
| 7031 | 110-17-8 | fumaric acid | 287 |
| 7032 | 110-16-7 | maleic acid | 138 |
| 7101 | 617-65-2 | l-glutamic acid | 160 |
| 7105 | 56-87-1 | lysine | 225Dec |
| 7116 | 110-94-1 | glutaric acid | 98 |
| 7123 | 77-92-9 | citric acid | 153 |
| 7299 | 334-48-5 | decanoic acid | 31.4 |
| 7315 | 143-07-7 | dodecanoic acid | 44 |
| 7331 | 57-10-3 | palmitic acid | 63 |
| 8112 | 73-22-3 | L-TRYPTOPHAN | 289Dec |
| 8190 | 56-40-6 | Glycine | 182 |
| 8201 | 141-82-2 | Malonic acid | 135 |
| 8213 | 52-90-4 | L-CYSTEINE | - |
| 8246 | 70-47-3 | L-ASPARAGINE | 234 |
| 8290 | 72-18-4 | Valine | 315 |
| 8396 | 61-90-5 | Leucine | 145Sub |
| 8418 | 59-67-6 | Niacin | 236 |
| 8421 | 98-92-0 | Niacinamide | 128 |
| 8657 | 495-69-2 | HIPPURIC ACID | 187 |
| 8965 | 150-13-0 | p-aminobenzoic acid | 187 |
| 8967 | 288-32-4 | imidazole | 90 |
| 8984 | 140-10-3 | trans-cinnamic acid | 133 |
| 9053 | 150-30-1 | DL-Phenylalanine | 283Dec |
| 10151 | 490-79-9 | 2,5-DIHYDROXYBENZOIC ACID | 199 |
| 10163 | 98-11-3 | BENZENSULFONIC ACID | 43 |
| 10415 | 6915-15-7 | malic acid | 131 |
| 11417 | 611-71-2 | mandelic acid | 119 |
| 16524 | 104-15-4 | p-TOLUENESULFONIC ACID | 106 |
| 16721 | 87-99-0 | Xylitol | 93 |
| 17155 | 50-69-1 | dextro-ribose | 87 |
| 17158 | 56-84-8 | laevo-aspartic acid | 270 |
| 17159 | 56-85-9 | laevo-glutamine | 185 |
| 17161 | 59-51-8 | dextro,laevo-methionine | 280Dec |
| 17167 | 71-00-1 | laevo-histidine | 287Dec |
| 17168 | 74-79-3 | laevo-arginine | 244Dec |
| 17259 | 107-95-9 | beta-alanine | 289 |
| 21229 | 56-45-1 | Serine | 228Dec |
| 21249 | 1118-68-9 | N,N-Dimethylglycine | 178 |
| 21254 | 72-19-5 | Threonine | 255Dec |
| 21296 | 73-32-5 | Isoleucine | 168Sub |
| 21930 | 59-46-1 | Procaine | 61 |
| 22142 | 117-39-5 | Quercetin | 314Dec |
| 22195 | 480-40-0 | Chrysin | 285 |
| 22200 | 501-36-0 | Resveratrol (trans) | 253 |
Which CCFs make co-crystal with indomethacin? HSP distance should be shorter than 12 so these compounds are candidates. The upper compounds means the higher possibility.
| 8984 | trans-cinnamic acid |
| 8112 | L-TRYPTOPHAN |
| 21930 | Procaine |
| 9053 | DL-Phenylalanine |
| 1200 | Caffeine |
| 22195 | Chrysin |
| 1052 | piperazine |
| 17161 | dextro,laevo-methionine |
| 1205 | 4-Aminopyridine |
| 54 | benzoic acid |
| 22200 | Resveratrol (trans) |
| 11417 | mandelic acid |
| 7299 | decanoic acid |
| 7315 | dodecanoic acid |
| 1225 | sebacic acid |
| 21296 | Isoleucine |
| 7331 | palmitic acid |
| 8396 | Leucine |
| 7105 | lysine |
| 603 | octadecanoic acid |
| 8290 | Valine |
| 8418 | Niacin |
| 17168 | laevo-arginine |
| 1204 | salicylic acid |
| 1232 | l-Tyrosine |
| 8967 | imidazole |
| 8657 | HIPPURIC ACID |
| 21249 | N,N-Dimethylglycine |
| 8213 | L-CYSTEINE |
| 8421 | Niacinamide |
| 17167 | laevo-histidine |
Which CCFs make dT(=T1-T2) large? These compounds are candidates.
| Hcode | name |
| 22142 | Quercetin |
| 1163 | ascorbic acid |
| 22195 | Chrysin |
| 22200 | Resveratrol (trans) |
| 1243 | Adenine |
| 10151 | 2,5-DIHYDROXYBENZOIC ACID |
| 1196 | Saccharin |
| 17155 | dextro-ribose |
| 16721 | Xylitol |
| 8965 | p-aminobenzoic acid |
| 917 | p-hydroquinone |
| 8112 | L-TRYPTOPHAN |
| 1232 | l-Tyrosine |
| 8657 | HIPPURIC ACID |
Which CCFs make T2 small?
| 10163 | BENZENSULFONIC ACID |
| 17155 | dextro-ribose |
| 16721 | Xylitol |
| 16524 | p-TOLUENESULFONIC ACID |
| 7299 | decanoic acid |
| 21930 | Procaine |
| 7024 | Glycolic Acid |
| 8967 | imidazole |
| 1163 | ascorbic acid |
| 7315 | dodecanoic acid |
| 7116 | glutaric acid |
| 8421 | Niacinamide |
| 7032 | maleic acid |
It is very hard to do all experiment. So the order is proposed by HSP, it is very meaningful.
2012.8.17
I got a mail from Automaxion (French Company). They are salling Co-Crystal screening Kit. They have 148 CCF entries and categorize into 1-4 and X kit. If user can choose CCFs with HSP distance, both Automaxion and clients are happy.
I already gave the software for the Japanese user so as they can do it by themselves. The translation of manual take me time so I put just executable program for the world user.
What you should to do is input HSP of your target compound. Then program will calculate the distance from CCF to target. And program also calculate CCF binary mixture volume ratio that make HSP distance shortest.
If you are using HTML5 enable browser, 4D CCF Designer program will run. For indomethacin case, please enter [20.4, 6.7, 4.7, 5.7] as target. Program calculate 148 HSP distance from indomethacin to CCFs. You can Copy & Paste to SpreadSheet and sort with distance. The branket value means melting point of CCF.
| CCF1 | distance |
| P-PHENYLBENZOIC ACID(228) | 2.733391157 |
| O-PHENYLBENZOIC ACID(114.3) | 2.751498068 |
| 4-Biphenylylacetic acid(160.5) | 3.649500577 |
| Acetyl Salicylic Acid(135) | 3.99386958 |
| P-NITROBENZOIC ACID(242) | 4.087376811 |
| benzoic acid(122.4) | 4.310990679 |
| 2-naphthol(123) | 4.314851992 |
| 1-Naphthol(95) | 4.336105098 |
You can choose shorter HSP distance CCFs and you can order them to Automaxion.
| CCF1 | Volume1 | CCF2 | Volume2 | distance |
| P-PHENYLBENZOIC ACID(228) | 71 | 6-Nitro-1H-indazole(182) | 29 | 0.747 |
| 4,4′-bipyridine(111) | 62 | 4,4'-DIHYDROXYBIPHENYL(283) | 38 | 0.824 |
| 4,4′-bipyridine(111) | 47 | 1-Naphthol(95) | 53 | 0.842 |
| P-PHENYLBENZOIC ACID(228) | 86 | Saccharin(228 dec) | 14 | 1.000 |
| 4,4′-bipyridine(111) | 67 | 2,7-Naphthalenediol(193) | 33 | 1.064 |
| isophthalic acid(347) | 41 | 4,4′-bipyridine(111) | 59 | 1.174 |
| 4,4′-bipyridine(111) | 71 | resorcinol(111) | 29 | 1.345 |
| 1-Hydroxy-2-naphthoic acid(195) | 40 | 4,4′-bipyridine(111) | 60 | 1.350 |
| P-PHENYLBENZOIC ACID(228) | 78 | p-benzoquinone(115.7) | 22 | 1.407 |
| P-PHENYLBENZOIC ACID(228) | 78 | Phthalimide(238) | 22 | 1.539 |
| 4-HYDROXYBENZOIC ACID(214.5) | 33 | 4,4′-bipyridine(111) | 67 | 1.554 |
| 4,4′-bipyridine(111) | 73 | p-hydroquinone(172.3) | 27 | 1.555 |
| P-PHENYLBENZOIC ACID(228) | 84 | succinic anhydride(119) | 16 | 1.583 |
You also will get binary mixture of CCFs. You will get much shorter HSP distance pair of CCFs. (For this binary search, I set only 48 CCFs those are listed in kit 1-4. Maybe, full set of program will be release soon.)
The indomethacin is used as medicine for stiff shoulder. I checked the compositions.
| Hcode | Name | dD | dP | dH | Score | RED | Mvol |
| 7107 | diisopropanolamine | 16 | 19.2 | 21.2 | 1 | - | 131.8 |
| 585 | 1,2-propanediol | 16.8 | 10.4 | 21.3 | 1 | - | 73.7 |
| 58 | benzyl alcohol | 18.4 | 6.3 | 13.7 | 1 | - | 103.8 |
| 18210 | diisopropyl adipate | 16 | 4.2 | 6 | 1 | - | 237.7 |
| 570 | isopropyl alcohol | 15.8 | 6.1 | 16.4 | 1 | - | 76.9 |
| 20359 | indomethacin | 20.5 | 9.4 | 11 | 283.1 | ||
| 1132 | l-Menthol | 16 | 4.7 | 9 | 177.5 | ||
| Skin | 17.12 | 3.03 | 13.89 |
The active ingredients are indomethacin and l-Menthol. Using “Sphere View Maker”, we can view of these compounds in Hansen Space.
Drag=Rotate, Drag+Shift=Larger/Smaller, Drag+Alt or Command(Window key)=Translate.
If you are using HTML5 enable browser such as Chrome or Safari,FireFox (IE9 have problems), you will see this Sphere. If you pick solvent, solvent name will appear.
The Small red Spheres mean Solvents. The large yellow shpere means Skin. The green sphere means indomethacin. The cyan sphere means l-Menthol. The position of l-Menthol, Skin and diisopropyl adipate in HSP space are very close. I want to know the skin pearmiablity of l-Menthol and diisopropyl adipate.
