WITEPSOL

FATTY BASES FOR SUPPOSITORIES

IOI Oleo GmbH

PHARMA
 Contents
1. Rectal therapy: history and future ........ 5 Alkaline impurities ............................................. 25
Ash ....................................................................... 25
2. Product range ....................................... 6
Water content ..................................................... 25
WITEPSOL H ................................................. 6
5. Processing ............................................ 26
WITEPSOL W ................................................. 7
General guidelines .............................................. 26
WITEPSOL S ................................................... 7
Processing methods ........................................... 26
WITEPSOL E .................................................. 8
Dosage in suppositories .................................... 27
3. Production and quality control ............ 10 Testing of suppositories ................................... 28
4. Test methods ........................................ 12 Challenges in suppository production ............ 30
Physical tests ....................................................... 13 References ........................................................... 32
Open-tube melting point .................................. 13 6. Overviews ............................................. 34
Solidication point ............................................. 14 WITEPSOL grades ......................................... 34
Refractive index .................................................. 15 Hard fat recommendations for active
Solid fat index ..................................................... 15 pharmaceutical ingredients................................ 36
Thin layer chromatography .............................. 16 Excipients for the
Gas chromatography ......................................... 17 pharmaceutical industry..................................... 38
Viscosity .............................................................. 19
Miscibility and solubility ................................... 20
Density ................................................................. 20
Caloric data ......................................................... 20
Chemical tests ..................................................... 21
Acid value ............................................................ 21
Hydroxyl value .................................................... 22
Iodine value ......................................................... 23
Peroxide value ..................................................... 23
Saponication value ........................................... 24 Abbreviations:

Unsaponiable matter ....................................... 24 JPE = Japanese Pharmaceutical Excipients

Heavy metals ....................................................... 24 Ph. Eur. = European Pharmacopoeia

September 2017 Iodine color number .......................................... 25 USP-NF = United States Pharmacopeia-National Formulary

Contents | 3
Rectal therapy: history and future
The application of remedies via the rectum can be traced back to antiquity.

It is reported that even the ancient Egyptians, ancient Indian physicians and the Mesopotamians used suppositories not only
as laxatives but also for the rectal treatment of pain, flatulence and heart spasms. The remedies were mostly mixed with
fats and then applied to wool plugs or pieces of linen cloth. As laxatives, these plugs were frequently also dipped in ox gall.

The scientific basis of rectal therapy was only established in the second half of the 19th century. This was based on the
investigations of the Stockholm anatomist Retzius, who proved in 1832 that some of the veins leaving the ampulla recti
directly lead to the vena cava inferior. This enables direct transportation of large amounts of the rectally administered
medicines into the blood circulation, bypassing the liver. With the introduction of cocoa butter as suppository base,
systematic investigations could be carried out more easily than before.

The increase of the fund of medicines and the spreading of the knowledge that the excipients also have an important
effect on the pharmacological activity of a medicine limited the applicability of cocoa butter for industrial production of
suppositories. Particular disadvantages were its chemical instability due to the high proportion of unsaturated glycerides as
well as compatibility problems between oxidation products (rancidity) and active compounds. Because of its very complex
polymorphic nature, cocoa butter is also not suitable for effective machine production.

The development of suppository compounds based on glycerides of saturated fatty acids of coconut and palm kernel oils
in the laboratories of the former Chemische Werke Witten, now IOI Oleo GmbH, made it possible to process a substanti-
ally larger number of active compounds according to specific biopharmaceutical and technological aspects.

The use of hard fats based on glycerides of saturated C12-C18 fatty acids is very common nowadays because of their ex-
cellent chemical and physical stability, their broad compatibility with nearly all active compounds, their neutrality towards
mucous membranes and their favorable processing properties even in high performance machines.

Water-soluble carriers (e.g. polyethylene glycols) are now only used in vaginal or ovular applications due to their irritation
potential on mucous membranes.

The suppository bases are described in Pharmacopoeias as Hard Fat, Adeps solidus (European Pharmacopoeia) or as Hard
Fat (USP-NF). As a result of numerous scientific investigations and publications, the tradename WITEPSOL has become
a synonym for modern suppository compounds.

Today, scientific interest in rectal therapy is still focused on several areas. It plays a role in the context of dissolution and
absorption of active compounds from suppositories, particularly in respect of sustained release and absorption promotion.
Additionally, it is a more convenient alternative to injections for patients. Following the latest scientific literature, rectal ther
apy has also proven to be a good choice for people with swallowing problems (e.g. children and elderly patients).

Therefore, it can be concluded that suppositories are still a valuable dosage form also for the future.

Rectal therapy: history and future | 5

 Product range
2 For the preparation of an optimal form of rectal medicine which has the required therapeutic action but can also be prepared
without difficulty in a pharmacy or on an industrial scale, a single grade is not sufficient. A range of WITEPSOL grades is
therefore available to meet the requirements in pharmaceutical technology, production, and also in biopharmacy, so as to achieve
WITEPSOL W
WITEPSOL products of series W are hard fats with hydroxyl values of 2050. They consist of a mixture of triglyceri-
the best possible effect in each case. To allow for a better overview of this huge variety, the WITEPSOL grades are divided into
des (6580%), diglycerides (1035%), and monoglycerides (15%). As a result of their composition, these WITEPSOL
four classes and, within these classes, are arranged in order of increasing melting point.
grades have a larger gap between melting and solidication points, they are less sensitive to shock cooling (more elastic),
solidify more slowly and can be readily processed both with automatic machines and with small-scale equipment. The
partial glyceride content also slows down the sedimentation of solids and promotes the absorption of less readily absorb
WITEPSOL H WITEPSOL products of series H are hard fats which are characterized by a low hydroxyl value. able active compounds.

WITEPSOL W WITEPSOL products of series W are hard fats which are characterized by a higher hydroxyl value.

WITEPSOL S WITEPSOL products of series S are special hard fats with addition of a non-ionic ethoxylated emulsifier. WITEPSOL W 32 melting point 3233.5 C HV = 4050

WITEPSOL E WITEPSOL products of series E are hard fats having melting points above body temperature. WITEPSOL W 25

melting point 33.535.5 C HV = 2030

WITEPSOL W 35

melting point 33.535.5 C HV = 4050

WITEPSOL W 45 melting point 33.535.5 C HV = 4050

WITEPSOL H WITEPSOL W 31 melting point 3537 C HV = 2535

WITEPSOL products of series H (except H 19) are hard fats with hydroxyl values up to 15. They mostly consist of triglyc
WITEPSOL W 45 is a special grade which is characterized by a higher monoglyceride content of up to 15%, which
erides with a portion of, at most, 15% of diglycerides and not more than 1% of monoglycerides. They are characterized
supports increased absorption promotion of active compounds and faster solidication.
by a very small gap between the melting and solidification temperatures, have only a minor tendency to the posthardening
phenomenon (maximum 1.5 C) (see page 35) and can be processed both with automatic casting machines and, on a small
scale, using the cream melting process (precrystallization) at casting temperatures around the stated melting point. Shock
cooling should be avoided. This series of grades also includes compounds having hydroxyl values (HV) between 0 and 5
which avoid interactions between the free OH groups and acidic active compounds (ASS, Diclofenac, etc.).
WITEPSOL S
WITEPSOL products of series S are special grades which contain particular auxiliaries in addition to the hard fat of
Compounds for suspension suppositories having a proportion of solid active compounds of over 25% pharmacopoeias.
WITEPSOL H 32 melting point 3133 C

HV = max. 3
They are used for the preparation of vaginal and rectal forms of medicines which require better wetting of mucous mem-
WITEPSOL H 12 melting point 3233.5 C

HV = 515
branes and enhanced dispersibility and are intended to promote absorption. The most important auxiliary is an ethoxylated
WITEPSOL H 19 melting point 33.535.5 C HV = 2030
cetylstearyl alcohol.

Compounds for suspension suppositories having a proportion of solid active compounds of less than 25%
WITEPSOL S 51 melting point 3032 C HV = 5570
WITEPSOL H 35 melting point 33.535.5 C HV = max. 3
WITEPSOL S 55 melting point 33.535.5 C HV = 5065
WITEPSOL H 5 melting point 3436 C HV = max. 5
WITEPSOL S 58 melting point 31.533.5 C HV = 6070
WITEPSOL H 15 melting point 33.535.5 C HV = 515

Compounds for suspension suppositories and lipophilic active compounds; for melting point correction

WITEPSOL H 37 melting point 3638 C HV = max. 3

6 | Product range Product range | 7

2 WITEPSOL E
WITEPSOL products of series E are hard fat compounds having a melting point above body temperature. They are used if
active compounds lower the melting point of the excipient because of their fat solubility.

They are characterized by their melting point and hydroxyl value. WITEPSOL E 75 additionally contains Cera alba.

WITEPSOL E 75 melting point approx. 38 C HV = max. 15

WITEPSOL E 76 melting point 3739 C HV = 3040

WITEPSOL E 85 melting point 4244 C HV = 515

8 | Product range Product range | 9

 Production and quality control
3 Production
WITEPSOL suppository compounds consist of glycerol esters of vegetable saturated fatty acids, mainly lauric acid.
Quality control
Raw material monitoring
Starting materials are puried, specially selected coconut and palm kernel oils from tropical plantations. In-process controls
Finished product analysis
After preliminary purication, the oils are cleaved in their fatty acids and glycerol by means of water at high pressure. The 100% batch testing and GMP-compliant documentation ensure complete traceability of our products.
fatty acid mixture is subjected to catalytic hydrogenation and subsequently to fractional vacuum distillation, and the low
molecular weight caproic, caprylic, and capric acids (C6 C10) are removed. The C12 C18 fatty acids are adjusted to the For release testing, the chemical parameters of fats according to the requirements of the European Pharmacopoeia are
correct mixture for the grade and esteried batchwise with puried and distilled glycerol. The fatty acid spectrum, the determined.
stoichiometry of the reaction mixture, and the reaction times and temperatures determine the properties of the product,
such as melting range, solid fat index, hardness, mono-, di-, triglyceride content (emulsiability/dispersibility), and viscosity. A supply evaluation system, continuous microbiological monitoring of the products and production plants, long term
stability testing, and further testing of application-oriented properties back the guarantee that WITEPSOL is always of
The crude reaction mixture is subsequently processed as follows: optimal pharmaceutical quality.
Alkali washing to remove free fatty acids (as soaps) and the catalyst (as fat-insoluble basic compounds)
Neutral washing to remove excess alkali
Drying in vacuum
Adsorptive treatment to remove chromogenic products and traces of catalyst
Steam distillation in vacuum and repeated drying
Deep-bed ltration under pressure

Some of the WITEPSOL grades are then mixed with emulsiers or consistency modifying waxes.

Directly prior to conversion into pellets or bulk material, another nal ne ltration is carried out.

WITEPSOL contains no stabilizing or decolorizing chemical additives which are not found in natural fats; it is produced
without solvents and virtually no microorganisms are present due to the production process.

10 | Production and quality control Production and quality control | 11

 Test methods
4 The European Pharmacopoeia (Ph. Eur.) requires the following tests for hard fat (Adeps solidus) which are described in
the table below:
Physical tests
Open-tube melting point (Ph. Eur. 2.2.15)
Definition
Identification
The open-tube melting point is the temperature at which the material starts to rise in the glass capillary.
Thin-layer chromatography (Ph. Eur. 2.2.27)

Comments
Purity tests Requirements Fats are not chemically uniform substances with a sharp melting point. They consist of a range of chemically similar gly-
Acid value (Ph. Eur. 2.5.1) max. 0.5 mg KOH/g cerides with sometimes very different melting points. The melting range which can be obtained is really a mixed melting
point. The end point of the above method marks the point at which the upward pressure of the fat column becomes greater
Hydroxyl value (Ph. Eur. 2.5.3, Method A) max. 50 mg KOH/g
than the adhesive force of the (molten) sample in the glass tube. At this temperature, the sample may have formed a clear
Iodine value (Ph. Eur. 2.5.4) max. 3 g J/100 g
melt, but need not have; an important factor is, inter alia, the lubricating action of the liquid fat components on the fat/
Peroxide value (Ph. Eur. 2.5.5) max. 3 meq O/kg glass interface.
Saponification value (Ph. Eur. 2.5.6) 210260 mg KOH/g

Alkaline impurities (Ph. Eur.) max. 0.75 ml 0.01 N HCl/10.00 g The pretreatment of the sample can also have an important inuence, since fats are present in different states of crystalliza
tion. The transitions between the modications are temperature and time-dependent. The above method does not necessarily
Sulphated ash (Ph. Eur. 2.4.14) max. 0.2%
determine the properties of the stable end modication, since transitions below 10 C take more than 24 hours. Before lling
Melting point (Ph. Eur. 2.2.15) 3045 C
the capillaries, WITEPSOL should be heated to above 60 C and stirred so as to ensure that all fat components are homo-
Nickel (Ph. Eur.) max. 1 ppm geneously distributed and the memory effect is avoided. The method is proved in practice and is sufcient for identication
of suppository bases. The accuracy and reproducibility require exact adherence to the conditions. Results differing by up to
0.8 C have been observed in ring tests at various laboratories.

12 | Test methods Test methods | 13

 Test methods
4 Physical tests
Solidication point (apparatus according to Ph. Eur. 2.2.18)
Refractive index
Since WITEPSOL contains only saturated glycerides, the refractive index is not very suitable for differentiation. Only in the
case of fats having high proportions of unsaturated fatty acids or partial glycerides, there are characteristic deviations from
Definition the values typical for hard fat.
The solidication temperature point is the highest temperature occurring during the solidication of a supercooled liquid.

Comments
Solid fat index (SFI)
An ideal cooling curve (Fig. 1) shows a minimum and a maximum which can be attributed to the cooling medium and the Definition
liberation of latent heat of solidication. However, depending on the material and the cooling conditions, it is possible that Percentage of solid glycerides in the fat mixture at a certain temperature.
only a saddle point is obtained. It is advantageous to record the temperature-time curve by means of a temperature sensor
and recorder. Comments
The solid fat index, in addition to the melting and solidication temperatures, is important in describing the state of aggre-
This method for determining the phase transition of suppository bases is somewhat less convenient to carry out than the gation and the phase transition of a fat. Even for the same melting point, the ratio of liquid and solid components below the
open-tube melting point (see page 13), but more advantageous for some fats. melting point may be different for various suppository bases: macroscopically the fats feel different. Suppositories should
also remain sufciently hard at 30 C and should not have a greasy surface (= too many liquid components). The aim should
be a SFI curve with the greatest possible gradient (Fig. 2, table 1).

WITEPSOL meets this requirement, since low melting glycerides of C8 /C10 fatty acids are removed (see pages 17 + 18,
gas chromatography).

Fig. 1: Typical solidication curve of WITEPSOL Fig. 2: Temperature dependence of the solid fat proportion in WITEPSOL H 15

Melting at 65.0 C 100

Solid fat content [%]

Cooling to 40.0 C, beginning of measurement
Temperature [C]

Cooling medium 20 C 80

60

Solidification point
40

20
0
0 5 10 15 20 25 30 35 40 45 50
Supercooled melt Time [min] Time [min]

14 | Test methods Test methods | 15

 Test methods
4 Physical tests
Table 1
Gas chromatography (GC)

I. Quantitative determination of the fatty acid composition

Solid Fat Indexproportion of solid components in WITEPSOL (DSC method) as a function of temperature [C]

The sample is transesterified with boron triuoride/methanol or sodium methoxide to give the methyl esters of the fatty
WITEPSOL 20 25 30 32.5 35 37.5 40 42.5 Open-tube melting point acids. After removal of the water-soluble components, the reaction mixture is directly injected. Column: Quartz-glass
H5 97 95 57 24 5 0 0 0 34.036.0 capillary (for example Carbowax chemically bound) 1530 m, temperature program to 250 C, injector/detector (FID)
temperature 320 C. For an exact quantitative determination of the fatty acid methyl ester peaks, the response factors
H 12 94 71 23 5 0 0 0 0 32.033.5
must be taken into consideration; however, if the percentage areas are equated to the percentages by weight, the error is
H 15 96 89 48 17 3 0 0 0 33.535.5
not greater than 10% relative. The C6C10 fatty acids originally present in the coconut/palm kernel oil are removed in the
H 35 82 59 27 14 4 0 0 0 33.535.5 production of WITEPSOL suppository bases. Thus, the hardness and the grip strength of suppositories are increased.
W 25 96 87 44 19 9 0 0 0 33.535.5

W 32 95 77 26 7 1 0 0 0 32.033.5 Higher melting WITEPSOL grades are distinguished from low melting ones by a shift of the fatty acid spectrum towards
palmitic (C16 ) and stearic (C18 ) acids.
W 35 95 84 36 15 2 0 0 0 33.535.5

W 45 96 88 32 13 2 0 0 0 33.535.5

S 55* 93 79 27 12 2 1 0 0 33.535.5
Fig. 3: Fatty acid composition of WITEPSOL H 15
S 58 * 86 68 27 17 2 0 0 0 31.535.5

E 75* 96 89 55 37 16 4 0 0 approx. 38.0

Retention time Quantity

Area
E 76 96 92 61 52 21 7 1 0 37.039.0 2.3 0.1 C
3.1 0.2 C
E 85 97 957 85 74 56 35 16 5 42.044.0
4.3 0.9 C
5.6 52.6 C
* Non-pharmacopoeial bases, containing special additives 6.5 20.7 C
7.4 11.7 C
8.3 13.7 C
9.0 0.2 C
Thin-layer chromatography (TLC)
For the identication of hard fats, the European Pharmacopoeia describes testing by thin-layer chromatography. The method 0 2 4 6 8 10 12
is suitable for separating mono-, di- and triglycerides from free glycerol. Unsaturated fats and fat-soluble impurities can some- Retention time [min]

times be seen alongside the spots typical for hard fats.

The conditions described do not give sufcient separation of the glycerides according to the chain length of their fatty
acids. Hard fats having a too high or too low melting point are not detected due to their different lipophilic properties.
Likewise, semiquantitative estimations of the partial glyceride content and the hydroxyl value are difcult.

TLC is also suitable for testing water-dispersable components (e.g. emulsiers). For this purpose, the sample must be shaken
with water and separated by using a more polar eluent (e.g. methylene chloride, ethanol, or water). Detection with iodine
gas. The various hard fat bases are differentiated in respect of their fatty acid and glyceride distribution by means of gas
chromatography.

16 | Test methods Test methods | 17

 Test methods
4 Physical tests
Gas chromatography (GC)
Viscosity
Molten WITEPSOL behaves approximately like a Newtonian liquid; the measured shear stress is almost linearly depen-
dent on the applied shear rate. The viscosity is lower for the H grades than for the partial glycerides containing W grades.
II. Quantitative determination of glycerides in WITEPSOL S grades have a slightly higher viscosity due to the emulsifier content (see Fig. 5).

For the C 12 C 18 fatty acids, glyceride peaks from C12 (monolaurate) to C 54 (tristearate) can be expected. The temperature dependence of the viscosity of WITEPSOL grades with the same melting range is shown in Fig. 6.
The differences are largest in the area of casting temperatures, since proportions of solid glycerides become noticeable
Assignment of the peaks requires reference materials; for an exact quantitative determination of the individual peaks, here (SFI).
response factors must be taken into account.
An incorporated active compound can considerably change the viscosity behavior of the system, since dose-dependent
WITEPSOL H 15 contains besides triglycerides (C36C54) monoglycerides (< 1%) and about 10% of diglyceri- physical interactions occur.
des, corresponding to a hydroxyl value of about 10. Higher hydroxyl values can be expected due to higher amounts of
diglycerides (for example WITEPSOL W 35) or additionally by means of an increased proportion of monoglycerides
(for example WITEPSOL W 45). Fig. 5: C
 omparison of the rheological behavior
= H 15 of pure WITEPSOL grades

Shear stress [%]

30 = W 35
= S 55

20

10

0
0 100 200 300 400 500
Shear gradient [1/s]

Fig. 4: Glyceride distribution of WITEPSOL H 15 Fig. 6: Viscosities as a function of temperature for suppository bases, exhibiting an open-tube melting point of:

WITEPSOLs with a melting range of 33.535.5C WITEPSOLs with a melting range of 3233.5C
Area

Monoglycerides Diglycerides Triglycerides 45 = H 15 45 = H 12

Viscosity [mPas]
Viscosity [mPas]
40 = W 35 40 = W 32
= S 55 = S 58
35 35

30 30

25 25

20 20

15 15

10 10
30 40 50 70 30 40 50 60 70
0 2 4 6 8 10 12 14 16 60
Retention time [min] Temperature [ C] Temperature [ C]

18 | Test methods Test methods | 19

 Test methods
4 Physical tests
Miscibility
Chemical tests
Acid value (AV)
All WITEPSOL grades give clear and homogeneous mixtures with each other. The resulting melting points correspond

Definition
approximately to the average mean. In practice, various WITEPSOL grades are often mixed, for example to compensate The acid value indicates the quantity, in mg, of KOH required to neutralize the free acids present in 1 g of fat.
melting point depressions caused by active compounds.
Comments
Solubility The acid value of the standard WITEPSOL grades is below 0.3. Grades containing beeswax or emulsier have higher values.

As a lipophilic material, WITEPSOL is soluble in petroleum, spirit, acetone, methylene chloride, ether and hot isopropanol;
Since free fatty acids are formed during the hydrolysis of glycerides, the acid value can be an indicator for the freshness
it is insoluble in water, ethanol, glycerol and polyethylene glycol.
of the fat. Because of the exceptionally low water content of WITEPSOL, a substantial increase in the acid value is not
expected even after some years if stored in accordance with directions.
Density
Determined by the Archimedes method 2.2.5 in the European Pharmacopoeia.
At 20 C the density of all WITEPSOL grades is about 0.96 g/cm3.

Caloric data
The specic heat of WITEPSOL is about:

0 C 1.9

10 C 2.0 J

20 C 2.4 g.K

60 C 2.1

J
The heat of fusion (2240 C) is about 138
g

20 | Test methods Test methods | 21

 Test methods Test methods
4 Chemical tests
Hydroxyl value (HV)
Chemical tests
Iodine value (IV)
Definition Definition
The hydroxyl value represents the quantity, in mg, of KOH required to neutralize the amount of acetic acid consumed The iodine value represents the number of grams of halogen (calculated as iodine) which are absorbed under the described
during acetylation by 1 g of WITEPSOL .
conditions by 100 g of WITEPSOL.

Comments
Comments
The hydroxyl value indicates the number of free hydroxyl groups in the suppository base. Since WITEPSOL is washed
The method determines unsaturated components in fats. Since the standard WITEPSOL grades contain only saturated fatty
free of glycerol, the HV is a degree of partial glycerides or hydroxyl groups containing additives (WITEPSOL S grades)
acids, the iodine value is below 3. Special grades can have an IV of up to 8 (see list of grades).
which are present.

Mono- and diglycerides can substantially influence the properties of the fatty base and the suppositories containing active
ingredients.

Peroxide value (POV)

T
 hey have an impact on the crystallization of the triglycerides and increase plasticity. Suppositories based on WITEPSOL
W grades are generally less brittle on shock cooling, but have a tendency towards greater posthardening (see page 35), i.e. Definition
a tendency for the melting point to increase. The peroxide value represents the quantity of peroxide, in milliequivalents of active oxygen, contained in 1000 g of WITEPSOL.
They increase the viscosity of the molten fats.
T
 hey have some surfactant properties: this can result in better dissolution, wetting, or dispersion of active compounds; tests Comments
must be carried out for chemical interactions with active compounds, in particular those containing carboxyl functions. Further The peroxide values of WITEPSOL are very low because of the products saturated nature and its stability against
more, the mucous membrane of the rectum can be made more permeable (higher bioavailability, absorption promotion). oxidation. The values found are therefore mostly not attributable to classical fat degradation, but to other products with
oxidation potential, for example Cetomacrogol in WITEPSOL S grades.

22 | Test methods Test methods | 23

 Test methods Test methods
4 Chemical tests
Saponication value (SV)
Chemical tests
Iodine color number (ICN)
Definition Definition
The saponication value represents the quantity, in mg, of KOH required to neutralize the free acids and to saponify the The iodine color number indicates the quantity, in mg, of iodine in an aqueous iodine/potassium iodide solution which
esters present in 1 g of fat. shows the same color intensity as a molten fat sample.

Comments Comments
The saponication value gives some indication of the fatty acid distribution of the triglyceride: the higher the SV, the lower The color of hard fat is caused by traces of chromogenic materials which can be formed by thermal processes during pro-
the average molecular weight, i.e. the more low molecular weight fatty acids are present. In most WITEPSOL types, the

duction. These are, for example, aldehydes, ketones, and their condensation products which cannot be completely removed
C8/C10 components have been removed. by distillation or by acid or alkali washing.

Such materials are largely removed by adsorption in the production process for WITEPSOL by treatment with bleaching
earth and activated carbon. WITEPSOL is not chemically bleached and contains no added brighteners which could im-
prove the color but not the purity. The iodine color number can, but need not, be a measure of the pharmaceutical quality
Unsaponiable matter of hard fat.
Comments
WITEPSOL contains very little unsaponiable matter, since the accompanying materials typically found in plants, such as
Alkaline impurities
waxes, sterols, higher alcohols, and hydrocarbons, are largely removed in the reesterication process. Special WITEPSOL
grades (e.g. S 55; E 75) contain beeswax or emulsiers and therefore more unsaponiable matter. Definition
Alkaline components determined by neutralization with HCI.

Comments
Alkaline components can arise from the rening process by the binding of free fatty acids with excess sodium hydroxide solution.

Due to the many refining steps, WITEPSOL contains only traces of alkaline impurities.

Sulphated ash
Definition
The sulphated ash test uses a procedure to measure the amount of residual substance not volatilized from a sample when
the sample is ignited in the presence of sulfuric acid. The test is commonly used for determining the content of inorganic
impurities in an organic substance.

24 | Test methods Test methods | 25

 Processing
5 General guidelines
WITEPSOL suppository bases have been established worldwide as replacements for cocoa butter. They have evident
The prerequisite is the following operating procedure:

1. M
 elting the compound above 60 C while stirring continuously to avoid memory effects caused by remaining crystalline
advantages with respect to: structures.
2. C
 ooling to a temperature which ensures ready suspension of the active ingredients. Depending on the quantity, particle
wide choice of melting points and hydroxyl values size and surface area of the active ingredients, this is 3540 C.
faster solidication 3. Incorporating the active ingredients into the melt while stirring continuously.
smaller melting point differences between crystal modications 4. Reducing the temperature until the viscosity increases appreciably. The pumpable consistency of the melt must be
stability against oxidation maintained by continuous stirring. This temperature can be equal to or a few degrees above the melting point of the fat.
substantial absence of interactions with active ingredients 5. A
 voiding stationary zones within the product stream, since at such points rapidly increasing solidication can interrupt
preventing sedimentation by selection of grade the ow, leading to an interruption in production.
release and absorption of active ingredients 6. The casting molds should be at room temperature.
7. After the lling procedure, the foil or lm strips must not be cooled suddenly, since a crystalline surface on the supposito-
ries can lead to the formation of cracks or casting channels. The temperature difference between the pumpable material
Processing methods and the rst cooling temperature of the cast suppositories should not be greater than 15 C.

Suppositories and pessaries are nowadays produced almost exclusively by a casting process on automatic machines. Other
previously used pressing processes (extrusion) or melt pressing processes have not remained competitive.
Dosage in suppositories
On automatic casting machines, the suppositories are pumped directly into preshaped plastic lms or aluminum foils. Casting The quantity of WITEPSOL needed to produce N suppositories can be calculated by means of a so-called displacement factor.
in metal molds, with subsequent sealing in cellophane, plastic lm, or aluminum foil is now only used for very small- scale
fabrication or on automatic machines which, although widespread in the past, are no longer manufactured today.
M= N (C-(f x A))

In contrast to cocoa butter processing, WITEPSOL can be subjected to an initial heat treatment (sterilization or similar)

M= quantity of base required for N suppositories in g
without any noticeable effect on the solidication behavior. N= number of suppositories

C= average capacity of a casting mold for pure base in g

Modern automated production machines give, if basic physical properties of the hard fats are taken into account, products
which meet the requirements of a desired drug form: f= displacement factor of the undissolved active ingredient

A= quantity of active compound per suppository in g

high content uniformity
uniform texture
The displacement factor indicates the number of grams of suppository bases which are displaced by 1 g of active ingredient.
f is the quotient of the densities of auxiliary and active ingredient.

26 | Processing Processing | 27
 Processing
5 Dosage in suppositories
The displacement factor of unknown materials is determined according to the formula:
Consistency
Suppositories must have a sufciently hard consistency to allow manual insertion, i.e. they should not start to melt at a
room temperature of about 20 C, even with the heat of the hand. In addition, it must be ensured that the suppositories
CW remain stable in shape at elevated room temperatures up to about 30 C and that sedimentation of the suspended active
f = +1 compound is avoided.
WxX
WITEPSOL therefore specically contains only those fatty acid esters which prevent softening below 30 C.
W = average weight of a suppository containing X% of active ingredient
Transesteried bases from coconut and palm kernel fats show distinctly lower hardness in this context. The medium chain-
To determine the capacity (C) of the casting mold (also known as the calibration value), WITEPSOL can be melted to a length fatty acid glycerides which are present here produce a negative effect because of their lower melting point.
clear melt, while the determination of W should be carried out by the cream melting process (avoidance of sedimentation
in the vessel containing the batch). The greater solubility of active ingredients at high temperatures can also affect the result. The desired small gap between good applicability and shelf life at elevated temperatures and rapid disintegration at body
temperature is also shown by the steep curves in the determination of the temperature-dependent solid-liquid behavior.
The displacement factor is not a constant of a material, but is dependent on the particle size, the crystal form, the wetta
bility, the solubility, and the concentration of the active ingredient.
Disintegration
Another dosage method (that of Mnzel) is as follows: Suppositories and pessaries must melt as quickly as possible after application. This avoids the sensation of a foreign body
The total active ingredient is mixed with a quantity of molten base which is less than that required for the production of the and rapidly releases the incorporated active ingredient to act locally or systemically. Testing of the melting behavior of the
intended number of suppositories and cast in such a way that none of the casting molds are completely filled. Subsequently, nished dosage form at body temperature is therefore an important criterion for quality. The measurement of the melting
the remaining volume is made up with pure base, the total weight of the suppositories is determined and the average weight point by capillary does not always correlate with this. The measurement of the melting behavior or more specifically the
is calculated. Subtraction of the weight of active ingredient used gives the required quantity of base for one suppository. disintegration time (Ph. Eur. 2.9.2) should be carried out at a very narrow temperature range of e.g. 37 0.1 C. Recom-
The suppositories produced in this way have an inhomogeneous distribution of active ingredient. Therefore, the supposi- mended instrument is the suppository penetration tester PM 30 (by SOTAX), according to method 2.9.22 (Softening Time
tories must be melted again and recasted, if they are to be further used. Determination of Lipophilic Suppositories) of Ph. Eur., apparatus B. The testing of the melting behavior of suppositories
also serves to choose the correct WITEPSOL type.

Testing of suppositories
In addition to visual examination for a uniform exterior, the absence of cracks, air bubbles, and other surface irregularities,
testing is carried out for uniformity of mass (max. 5% of the average mass in accordance with 2.9.5 of the European
Pharmacopoeia) and uniformity of content (+ 15% of the average content in accordance with 2.9.6 of the European
Pharmacopoeia).

Additional tests are:

consistency
disintegration
release of active compound in vitro

28 | Processing Processing | 29
 Processing
5 Testing of suppositories
The effects of the active compounds can further intensify the crystallographic change in the excipient fat so that supposi-
Dimples, sink holes
This fault in appearance occurs frequently and has the same causes as mentioned above: the fat in the center solidies more
slowly and draws, as a result of its contraction, material from above into the core.
tory bases having different melting points should always be used at the beginning of formulation work.

The use of a WITEPSOL grade having a melting point below 33.5 C can be important for the optimal melting time of Matt surface
the nished suppository. Fat bloom consists of crystalline fat formed by diffusion on the surface. If the gap between surface and packing lm or foil
is small (low contraction), this phenomenon typical for fats can usually not develop. It is therefore advantageous to use
Dissolution testing of active ingredients in vitro compounds showing low contraction or a process method using precrystallized fat (see above).

For dissolution testing, methods described in Ph. Eur. 2.9.3 can be adapted for suppositories.
Inhomogeneous distribution of active ingredients
If sedimentation of the active ingredient occurs despite stirring, the viscosity of the melt is usually too low. Reducing the
Challenges in suppository production temperature of the mixture or increasing the cooling after casting or adding viscosity enhancers (e. g. Aerosil) may solve

Cracks the problem.

Cracks (mostly longitudinal) are caused by stresses in the solid fat which arise from the different cooling rates at the exterior
and within the mold. These visible damages can be avoided by Thickening of the molten mixture
Some active ingredients can, in high doses, form gel-like masses with fat which do not solidify well. This phenome-
selecting an elastic fat or non, which has not been fully explained, is probably caused by dissolution of the crystal surface by partial glycerides.
lowering the casting temperature and increasing the cooling temperature, which makes the fat solidify more homoge- Possible solutions are fatty bases having a low hydroxyl value, different particle size distributions of the active compound,
neously. or viscosity-lowering additives (e. g. lecithin).

Transverse cracks can also be caused by mechanical stressing of the solidifying suppository, for example in the sealing pro-
Posthardening
cess, if the mold is lled excessively and pressure is applied to the compound.
The melting point of cast suppositories can increase as a function of the fat type, the active ingredients, the method of
production, and the storage conditions and time. The cause is a change in the crystal modication of the solid fat. The
transition from the unstable -modication which is predominant in the fresh state, to the stable -modication proceeds
via intermediate stages and can occur very slowly for example at low storage temperatures.

30 | Processing Processing | 31
 Processing
5 Challenges in suppository production
A stable end modification and a constant melting point can be achieved by applying a suitable tempering process during
manufacturing. The cream melting process, long known in the preparation of pharmaceuticals, has not lost its signicance
in the industrial mass production of suppositories: the lowest possible casting temperature of the stirred compound and
the highest possible cooling temperature are ideal. In this way, a high proportion of the stable end modication is produced
from the beginning, and posthardening is thereby reduced.

Further reading
Recommended books with further references relating to pharmacological and technological aspects of rectal therapy:

[1] D
 iepgen, P. Das Analzpfchen in der Geschichte der Therapie [The anal suppository in the history of therapy]
G. Thieme Verlag, Stuttgart 1953

[2] Thoma, K. Arzneiformen zur rektalen und vaginalen Applikation [Drugforms for rectal and vaginal applica-
tion] Werbe- u. Vertriebsges. Dtsch. Apoth. [Advertising and Business Association of German Pharmacists],
Frankfurt 1980

[3] Nnberg, E. (Editor) Hagers Handbuch der pharmazeutischen Praxis, Band 2 Methoden [Hagers Handbook of
Pharmaceutical Practice, Volume 2 Methods] Springer Verlag, Berlin, Heidelberg 1991

[4] Bosch, P.; Loth, H. Solidification of Molten Hard Fats in Dependence on the Chemical Composition and Thermal
Pretreatment, [ Die Pharmazeutische Industrie, EditioCantor Verlag, Pharm. Ind. 58, 2, 161166 (1996)]

32 | Processing
 Overviews
6 WITEPSOL grades
Description
Suppository bases according to the current monographs Hard Fat, Adeps solidus Ph. Eur. and Hard Fat USP-NF. They are
white, odorless hard fats in pastille shape which comprise of glycerides of plant origin; tailored to the point by de novo synthesis.

Ascending Hydroxyl Acid Iodine Peroxide Saponification Alkaline Nickel Sulphated Unsaponifiable
melting value value value value value impurities ash matter
point [C] [mg KOH/g] [mg KOH/g] [g I/100g] [meq O/kg] [mg KOH/g] [ml HCI/2g] [ppm] [%] [%]
Method Ph. Eur. 2.2.15 Ph. Eur. 2.5.3 Ph. Eur. 2.5.1 Ph. Eur. 2.5.4 Ph. Eur. 2.5.5 Ph. Eur. 2.5.6 Ph. Eur. Ph. Eur. Ph. Eur. 2.4.14 Ph. Eur. 2.5.7 Method

WITEPSOL H 5 34.036.0 max. 5 max. 0.2 max. 2 max. 1 235245 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL H 5
WITEPSOL H 12 32.033.5 515 max. 0.2 max. 3 max. 1 240255 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL H 12
WITEPSOL H 15 33.535.5 515 max. 0.2 max. 3 max. 1 230245 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL H 15
WITEPSOL H 19 * 33.535.5 2030 max. 0.2 max. 7 max. 3 230240 max. 0.15 max. 1 max. 0.05 max. 0.6 WITEPSOL H 19*
WITEPSOL H 32 31.033.0 max. 3 max. 0.2 max. 3 max. 1 240250 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL H 32
WITEPSOL H 35 33.535.5 max. 3 max. 0.2 max. 3 max. 1 240250 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL H 35
WITEPSOL H 37 36.038.0 max. 3 max. 0.2 max. 3 max. 1 225245 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL H 37
WITEPSOL W 25 33.535.5 2030 max. 0.3 max. 3 max. 1 225240 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL W 25
WITEPSOL W 31 35.537.0 2535 max. 0.3 max. 3 max. 1 225240 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL W 31
WITEPSOL W 32 32.033.5 4050 max. 0.5 max. 3 max. 1 225245 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL W 32
WITEPSOL W 35 33.535.5 4050 max. 0.3 max. 3 max. 1 225235 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL W 35
WITEPSOL W 45 33.535.5 4050 max. 0.3 max. 3 max. 1 225240 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL W 45
WITEPSOL S 51 * 30.032.0 5570 max. 0.5 max. 8 max. 4 215230 max. 0.15 max. 1 max. 0.05 max. 0.5 WITEPSOL S 51*
WITEPSOL S 55* approx. 35** 5065 max. 1.0 max. 3 max. 3 215230 max. 0.15 max. 1 max. 0.05 max. 2.0 WITEPSOL S 55*
WITEPSOL S 58 * 31.533.0 6070 max. 1.0 max. 7 max. 4 215225 max. 0.15 max. 1 max. 0.05 max. 2.0 WITEPSOL S 58*
WITEPSOL E 75* approx. 38** max. 15 max. 1.3 max. 3 max. 1 220230 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL E 75*
WITEPSOL E 76 37.039.0 3040 max. 0.3 max. 3 max. 1 220230 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL E 76
WITEPSOL E 85 42.044.0 515 max. 0.3 max. 3 max. 1 220240 max. 0.15 max. 1 max. 0.05 max. 3.0 WITEPSOL E 85
Monographs
Ph. Eur. 3045 max. 50 max. 0.5 max. 3 max. 3 210260 max. 0.15 max. 1 max. 0.2 Ph. Eur.
USP 2744 max. 70 max. 1.0 max. 7 215255 max. 0.15 max. 0.05 max. 3.0 USP
JPE 3045 max. 70 max. 2.0 max. 3 210255 max. 3.0 JPE

* WITEPSOL grades H19, S51, S55, S58 and E75, respectively, are mixtures of hard fats (according to Ph. Eur.) and additives.
** Due to additive beeswax, the ascending melting points are hard to reproduce (adhesion at the glas capillary). The solidication points are more precise.
They are for WITEPSOL E 75 = 3436.5 C, for WITEPSOL S 55 = 2833 C.

34 | Overviews Overviews | 35
 Overviews
6 Hard fat recommendations for commonly used
active pharmaceutical ingredients

WITEPSOL H 15 / W 35 WITEPSOL E 75 / E 85

Actives for malaria treatment Analgesics

Anesthetics Anesthetics

Anti-inflammatory substances Antihypertonics

Antidepressants (alkaloids) Steroidal antirheumatics (corticosteroids)

Antiemetics

Antiepileptics (barbiturates) WITEPSOL S 51 / S 58

B vitamins Female hormones

-lactam antibiotics Spermicides

Bronchodilatators

Expectorants

Male hormones

Nonsteroidal anti-inflammatory drugs

Steroidal antirheumatics (corticosteroids)

WITEPSOL W 45

Actives for hemorrhoidal treatment

Anti-inflammatory substances for

treatment of Crohns disease and related indications

Antimycotics

-lactam antibiotics
Laxatives

Nonsteroidal anti-inflammatory drugs

Opioids such as Tramadol and related substances

36 | Overviews
 Overviews
6 Excipients for the pharmaceutical industry, also manufactured
by IOI Oleo GmbH
Applications and functions

Topical preparations Product Injectable preparations (i.m., i.v., intramammary) Product

Ointment base O/W SOFTISAN 601 Oil components MIGLYOL 810 N, 812 N

Fatty bases SOFTISAN 154, 378 Lipid crystals DYNASAN 110118

Oil components MIGLYOL 128, 810 N, 812 N, 818, 829

Emulsifiers O/W IMWITOR 372 P, 375, 960 K Eye and nasal preparations Product

Emulsifiers W/O IMWITOR 491, 600, 900 K, 900 (F) P, 948, 990 Fatty bases SOFTISAN 378, 601

Solubilizers and wetting agents SOFTIGEN 767 Oil components MIGLYOL 810 N, 812 N, 818, 829, 840

Absorption promoters IMWITOR 308, 742, 988 Emulsifiers O/W IMWITOR 372 P, 375, 960 K

Consistency and stability regulators MIGLYOL Gel B, T, 840 B DYNASAN 110118 SOFTISAN 645, 649 Emulsifiers W/O IMWITOR 491, 900 K, 900 (F) P

Skin-protective agent SOFTIGEN 701

Spreading agents MIGLYOL 812 N, 840

Rectal and vaginal preparations Product

Suppository bases WITEPSOL (all grades)

Consistency regulators MIGLYOL Gel B, T, 840 B DYNASAN 110118 SOFTISAN 645, 649

Crystallization initiators DYNASAN 116, 118

Dispersing agents IMWITOR 491, 900 K, 900 (F) P

Absorption promoters IMWITOR 308, 742, 988

Protective agent SOFTIGEN 701

Oral preparations Product

Retarding agents SOFTISAN 154 DYNASAN 110118 IMWITOR 900 K, 900 (F) P

Tablet lubricants DYNASAN 110118

All registered trademarks displayed in this brochure are the property of the IOI Oleochemicals Group. Users of this brochure
Polishing agent MIGLYOL 812 N
are not permitted to use these trademarks without the prior written consent of their proprietor. All rights are reserved. All
Fatty bases SOFTISAN 154, 378 rights not expressly granted are reserved.
Oil components MIGLYOL 810 N, 812 N, 818, 829, 840

Dispersing agents IMWITOR 491, 900 K, 900 (F) P We reserve the right to make any changes as a result of technological progress or developments. No guarantee or warranty
is implied or intended as to any particular properties of our products. The customer is not exempted from the obligation
Absorption promoters IMWITOR 308, 742, 988
to conduct careful inspection and testing of incoming goods. Reference to trademarks used by other companies is neither
Consistency regulators SOFTISAN 378
a recommendation, nor should it give the impression that products of other companies cannot be used. All IOI Oleochemicals
business transactions are exclusively governed by our General Business Terms and Conditions please see www.ioioleo.de
(Terms and Conditions.)

38 | Overviews Overviews | 39
 Contact
IOI Oleo GmbH
Hamburg, Germany | +49 40 28 00 31-0 | [email protected] | www.ioioleo.de