Hansen Solubility Parameter (HSP) and Gall Stone

HSP Application note #34

2010.4.23

HSPiP Team Senior Developer, Dr. Hiroshi Yamamoto

I found the Gall Stone solubilizer paper.
It is written in Japanese, so please refer to USP-3,882,248.
Some Terpene compounds have very good solubility of Gall Stone and it is very safety.
In the paper, the author wrote the reason terpene dissolve Cholesterol because "like dissolve like".
The concentration of solution is,
d-limonene 1090
Chloroform 2222
Ethyl ether 3571

d-limonene, maybe we can say "like dissolve like" from chemical structure.
But Chloroform and ethyl ether are not like chemical structure.
So, we will show Hansen Solubility parameter's "like dissolve like" with this example.

Hansen Solubility Parameters (HSP)

Hansen Solubility Parameters(HSP) were developed by Charles M. Hansen as a way of predicting if one material will dissolve in another and form a solution. They are based on the idea that "like dissolves like" where one molecule is defined as being 'like' another if it bonds to itself in a similar way.
Specifically, each molecule is given three Hansen parameters, each generally measured in MPa0.5:
dD:The energy from dispersion bonds between molecules
dP:The energy from dipolar intermolecular force between molecules
dH:The energy from hydrogen bonds between molecules.
These three parameters can be treated as Vector for a point in three dimensions also known as the Hansen space. The nearer two molecules HSP Vector are in this three dimensional space, the more likely they are to dissolve into each other.

What can perhaps be surprising is that one can assign HSP to so many different things. Gases like carbon dioxide, solids like carbon-60, sugar, and biological materials like human skin, depot fat, DNA, and even some proteins all have HSP. The list can be continued with drugs, polymers, plasticizers, and in fact any organic material and even many inorganic materials like salts. The only requirement for an experimental confirmation is that the material must behave differently in a sufficient number of test solvents upon contact.

Pirika JAVA Demo Applet calculate HSP. HSPLight is available here.
Please refer to e-Book of HSPiP if you want know more about HSP.
About the Power Tools that handle HSP more effectively.

We checked WikiPedia about Cholesterol, and got Smiles and solvents information.
At first, we need to get HSP of Cholesterol.

HSPiP(Hansen Solubility Parameters in Practice)

The first edition of HSPiP that appeared in November, 2008, greatly enhanced the usefulness of the Hansen solubility parameters (HSP).

The HSP values of over 1200++ chemicals and 500 polymers are provided in convenient electronic format and have been revised and updated using the latest data sources in the second edition (March, 2009).

A third edition of the HSPiP appeared in March, 2010. There are now 10,000 compounds in the HSP file which also includes data on density, melting point, boiling point, critical parameters, Antoine constants and much more. The user is able to carry out many different sorts of optimisations of solubility, evaporation, diffusion, adhesion, create their own datasets (automatically if required) and explore the huge range of applications for HSP in coatings, paints, nanoparticles, cosmetics, pharma, organic photovoltaics and much more.

The 3rd Edition v3.1 was released on 12 December 2010. Current users can upgrade free (now v3.1.09) by downloading the latest .msi installer from http://hansen-solubility.com

The 4th Edition v4.0.x was released on 2 Jan. 2013. The Current users can upgrade with free charge.

2013.1.28 The Visual How to manual of HSPiP. You can understand what HSPiP can do.
Please check the Functional Group List whether your targets are available with HSPiP.
How to purchase HSPiP
2013..1.2 The HSPiP ver. 4 include Power Tools for HSPiP power user.

In HSPiP we found this compound HCode(Hansen code) 16840. But official HSP is not exist.
In that case, we use Y-MB to get calculated HSP.
Only smiles structure ([C@H](C)([C@@H]4[C@]1(C)[C@H]([C@H]3[C@H](CC1)[C@]2(CC
[C@@H](CC2=CC3)O)C)CC4)CCCC(C)C) of Cholesterol is needed. Instantly we got [17.4, 2.6, 5.7] volume 402.3.

Smiles(Simplified Molecular Input Line Entry Syntax)

SMILES is a string obtained by printing the symbol nodes encountered in a depth-first tree traversal of a chemical graph.
"Organic subset" of B, C, N, O, P, S, F, Cl, Br, and I, brackets can be omitted.
Branches are described with parentheses, as in CCC(=O)O for propionic acid
Double and triple bonds are represented by the symbols '=' and '#'
Ring closure labels are used to indicate connectivity between non-adjacent atoms in the SMILES

Pirika JAVA Demo Applet getting Smiles. Draw2Smiles is available here.
Now we have Power Tool "Draw 2 Smiles", GUI HTML5 software on HSPiP ver. 4.

Y-MB Properties Estimation

Y-MB break Smiles into correspponding Functional Groups and Estimate various Properties. These estimation schemes are come from Pirika technologies.

Pirika JAVA Demo Applet calculate Properties. PirikaLight is available here.
Now we have Power Tool "Y-Predict", GUI HTML5 software on HSPiP ver. 4.

Then we checked solvents listed in WikiPedia.

Hcode	name	Solubility	dD	dP	dH	Volume
16840	CHOLESTEROL		17.4	2.6	5.7	402.3
156	CHCl3	++++	17.8	3.1	5.7	80.5
255	diethyl ether	++++	15.49	2.9	4.6	104.7
306	1,4-dioxane	+++	17.5	1.8	9	85.7
325	ethyl alcohol	++	15.8	8.8	19.4	58.6
	petroleum-ether	++	15	0	0	125
7	Acetone(Cold)	++	15.5	10.4	7	73.8
696	Water	X	15.5	16	42.3	18
52	Benzen		18.4	0	2	89.5
417	Hexane		14.9	0	0	131.4
456	methanol		14.7	12.3	22.3	40.6
7967	Isopropyl myristate		16.2	2	4	322.8

We did not have petroleum ether official value but maybe this compound(s) (mixture of hydrocarbons) HSP is [15, 0, 0].
With this results, Chloroform[17.8, 3.1, 5.7], diethyl ether [15.49, 2.9, 4.6] and isopropyl myristate[16.2, 2, 4] have very similar HSP to Cholesterol[17.4, 2.6, 5.7].
When HSP says "like dissolve like", we believe similar HSP vector dissolve similar vector.
You can easily understand this result.

HSP Distance

To calculate the distance (Ra) between Hansen parameters in Hansen space the following formula is used:

HSP distance(Ra)={4*(dD1-dD2)2 + (dP1-dP2)2 +(dH1-dH2)2 }0.5

Then how about the Terpene?

Hcode	name	Solu bility	CAS	dD	dP	dH	Volume	C:CalcHSP
11440	Myrcene	2	123-35-3	16	2.2	5.1	171.6
	Ocimene	2	502-99-8
17042	Linalool	2	78-70-6	16.5	2	9.1	179.8
9093	Geraniol	2	106-24-1	16	4.7	11	173.4
8088	Nerol	2	106-25-2	16.7	4.5	11.3	175.8
9098	Citronellol	2	106-22-9	16	4.7	10.7	182.3
17455	Artemisia Keton	1	546-49-6	15.9	5.8	5.1	176.8	C
16642	Citral	2	5392-40-5	16.3	2.3	6.2	171.3
18129	Citronellal	2	5949-05-3	16.2	5.9	5.2	177.4	C
11459	Linalyl acetate	1	115-95-7	16	2.8	5.5	219.3
1253	Limonene	3	5989-27-5	17.2	1.8	4.3	162.9
19861	Dipentene	3	68956-56-9	16.7	2.2	4	161.4	C
7635	Terpinolene	3	586-62-9	16.9	1.8	4.1	159.2	C
7636	Phellandrene	2	99-83-2	16.5	1.6	3.9	165.3	C
10445	Terpinene	3	99-85-4	17.2	1.8	4.3	159.7
	Sylvestrene	2	1413-20-3	16.6	3	4.1	163.1	C
8064	Terpineol	2	98-55-5	17	5.3	10.9	165.2
17749	Perillaldehyde	2	2111-75-3	17.1	6.9	5.9	156.7	C
16590	Carvone	3	2244-16-8	18	5.6	6.4	155.7
1133	Pulegone	2	89-82-7	17.5	8.9	5.5	162.9
17199	piperitone	2	89-81-6	17	6.2	4.5	167	C
8957	Menthone	3	14073-97-3	17	8.1	4.4	172.3
1135	1,8-Cineol	3	470-82-6	16.7	4.6	3.4	167.5
17350	1,4-Cineole	3	470-67-7	17.1	3.6	3.7	168.5	C
	Sabinene	1	2009-00-9
	piene	2
18978	Umbellulone	1	24545-81-1	17.7	6.6	4.1	155.1	C
18002	Farnesol	1	4602-84-0	16.4	3.8	7.7	249.2	C
17322	Nerolidol	1	142-50-7	16.4	2.7	8.7	255.6	C
17385	Bisabolene	1	495-61-4	16.7	2.2	4	236.2	C
17384	Zingiberene	1	495-60-3	16.6	1.4	4.1	237.4	C

With this case, we also found Limonene, Dipentene, Terpinolene and Terpinene have very similar HSP vector to Cholesterol.

Hansen Sphere

To determine if the parameters of two molecules (usually a solvent and a polymer) are within range a value called interaction radius (R0) is given to the substance being dissolved. This value determines the radius of the sphere in Hansen space and its center is the three Hansen parameters.

From version 3.1.X, Double Spheres function is available.

Pirika provide JAVA 3D Demo Applet to browse the Sphere(s).
The HTML5 Sphere Viewer examples are available here.
Now we have Power Tool "Sphere Viewer", GUI HTML5 software on HSPiP ver. 4.

We had several exceptions.
Bisabolene, Zingiberene have almost same HSP but not so much dissolve.
We need more accurate examination, but these compounds have much larger Molecular Volume. That may the one of the reason.

Once we have these results, we can examine a lot of things.
For example, some food, drinks are said to reduce Cholesterol, we want to know the HSP of effective chemicals.
Some fiber in food are said to reduce Cholesterol. Where Cholesterol absorbed?
Maybe similar HSP part exist in fiber.

Some children need Cholesterol, but Cholesterol is hard to dissolve triglyceride.
How can we design triglyceride?
You can do with HSPiP.

GC data of class 1, class 2 solvents in Q3C:
HSP and Tamiflu: Solubility parameter of Tamiflu or other H1N1 antiviral compounds
HSP for Rabbit: How to design eau de Cologne for rabbit. what LD50(skin, rabbit) means.
HSP and logP: logP, logKow, it is just HSP volume.
HSP and Carcinogenicity: SOM(self organization map) analysis of Poly-chlorinated compounds
HSP and Endocrine Disruptor: categorize by SOM.
HSP and AntimicroBial. Sulfa Drugs and other kind of Drugs.
Gall stone solubilizer: How to dissolve Cholesterol base Gall Stone.
Caco-2 cell monolayer apparent Permeability:SOM analysis