Hansen Solubility Parameter (HSP) and LD50(skin,rabbit)

HSP Application note #16

2010.2.15

HSPiP Team Senior Developer, Dr. Hiroshi Yamamoto

This time, I will write about LD50 (but not prediction of LD50).
LD stands for "Lethal Dose". LD50 is the amount of chemicals, given all at once, that causes the death of 50% of a group of test animals.
This test is short-term poisoning potential (acute toxicity) test.

We have more than 10000 compounds database for HSPiP ver.3, and compiled LD50 information. Most popular oral LD50 test is for Rat and most popular skin LD50 test is for Rabbit.

And I found one thing.

Some compounds are very toxic for LD50 (oral,Rat) and also toxic for LD50(skin,rabbit).
Some compounds are not so toxic for LD50(skin,rabbit).
Can you imagine which structure is which?

I completely miss understand.

I choose LD50(oral, Rat)<180
The first list is Both toxic for LD50 (oral,Rat) and LD50(skin,rabbit).
These are water soluble compounds.
I've thought hydrophobic materials are toxic.

CAS	name	LD50Rat	LD50 (skin,rabbit)	logP	logS
75-86-5	acetone cyanohydrin	18.65	15.8	-0.03	2.00
107-19-7	propargyl alcohol	20	16	-0.38	2.00
107-11-9	allylamine	102	35	0.03	2.00
107-18-6	allyl alcohol	64	45	0.17	2.00
107-07-3	2-chloroethanol	71	67	0.03	2.00
1464-53-5	Butadienedioxide	78	89	-0.28	2.00
111-44-4	Di-(2-Chloroethyl) Ether	75	90	1.29	0.24
			Average	0.12	1.75

CAS	name	LD50Rat	LD50 (skin,rabbit)	logP	logS
591-87-7	allyl acetate	130	1021	0.97	0.31
109-75-1	vinylacetonitrile	115	1410	0.40	0.53
13952-84-6	sec-butylamine	152	2500	0.74	1.05
79-22-1	methyl chloroformate	60	7120	0.14	0.97
126-98-7	methacrylonitrile	120	12500	0.68	0.41
			Average	0.59	0.65

And in second table, I show the list of very toxic for LD50(oral, Rat) and not so toxic for LD50(Skin Rabbit).
These compounds have intermediate solubility to water.
(There are many compounds between 100<LD50(skin, rabbit)<1000 but hard to understand, so do not show the data.)

With this result, Water soluble materials are go into Sweat pore and go into blood.
So, it is same toxicity with LD50 (Rat) and LD50(skin,rabbit).
And maybe second category materials are very easily dissolve to subcutaneous fat and very hard to release.
It is something like HPLC Solid Phase(Octa decyl silyl) = Fat and moving phase=Blood.
If it come to HPLC, it become much better think with HSP.

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.

If you have Smiles structure and HSPiP software, Y-MB function will calculate HSP immediately.

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.

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.

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.

name	dD	dP	dH	Volume
acetone cyanohydrin	16.76	14.99	18.53	87.8
propargyl alcohol	16.13	8.45	20.00	61.8
allylamine	15.18	6.40	9.87	74.5
allyl alcohol	15.57	8.08	17.71	69.2
2-chloroethanol	17.21	11.24	17.49	67.5
Butadienedioxide	17.65	10.22	7.88	80.8
Di-(2-Chloroethyl) Ether	17.18	8.25	4.90	118.3
	16.52	9.66	13.77	80.0

name	dD	dP	dH	Volume
allyl acetate	15.81	5.05	7.59	108.4
vinylacetonitrile	15.78	11.45	5.59	81.8
sec-butylamine	14.99	4.39	7.18	98.8
methyl chloroformate	16.71	7.47	9.10	76.2
methacrylonitrile	15.74	11.79	5.36	82.3
	15.81	8.03	6.96	89.5

I show you calculated HSP values for these compounds.
And I think subcutaneous fat of Rabbit is [15.81, 8.03, 6.96].
(relatively high dP, dH for fat, I think)

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.

I know molecular volume is also very important. Larger molecule will not permeate skin.
But such molecule is not so toxic for LD50(oral, Rat)

Once we get this value, we can do a lot for Rabbit.
For example, eau de Cologne for Rabbit.
Rabbit (and cat) never take a bath. They dislike water.
That means bad smell. So if you want to design eau de Cologne for Rabbit, if choose fragrance HSP near [15.81, 8.03, 6.96], then that fragrance easily dissolve to subcutaneous fat and last very long.
I searched fragrance FOR RABBIT in our database. 3 compounds are matched.

CAS: 6789-80-6
Zeon make this compound for fragrance.
Odor description: vegetable green.

CAS: 5436-21-5
odor description:ethereal musty nutty alcoholic bitter

CAS: 4440-65-7
Odor description: leafy green stem tomato melon apple

If you want to design some medicine that release drug very slowly FOR RABBIT, it is very good idea to set drug HSP [15.81, 8.03, 6.96] and absorbed via skin.

If you want to design cream for dry skin RABBIT, These structure will work very well I believe.
(Please let me know if you try this)

HSPiP has the function of predict logP and logS.
So, every data is included in HSPiP what you want to do FOR RABBIT that concern about solubility. please try to use HSPiP.

<p>Please Use HTML5 Browser</p>

If you want to know how to draw molecules, please refer to Power Tools applications. The full version of this estimation routine is implemented into Y-Predict Powert Tools in HSPiP ver. 4.

You can apply HSP technology to human subcutaneous fat, But unfortunately, I have no data of LD50(skin, human).
But soon FFE project reveal these secret.