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Efficient throughput method for hygroscopicity


classification of active and inactive
pharmaceutical ingredients by water vapor
sorption analysis

Article in Pharmaceutical Development and Technology · October 2011


Impact Factor: 1.2 · DOI: 10.3109/10837450.2011.618947 · Source: PubMed

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Pharmaceutical Development and Technology, 2013; 18(2): 348–358
© 2013 Informa Healthcare USA, Inc.
ISSN 1083-7450 print/ISSN 1097-9867 online
DOI: 10.3109/10837450.2011.618947

RESEARCH ARTICLE

Efficient throughput method for hygroscopicity classification


of active and inactive pharmaceutical ingredients by water
vapor sorption analysis
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Vasudha Murikipudi, Piyush Gupta, and Vaibhav Sihorkar

Pharmaceutical Development, Aurigene Discovery Technologies Limited, Bollaram Road, Miyapur, Hyderabad,
Andhra Pradesh, India

Abstract
The conventional method of hygroscopicity determination proposed by Callahan and co-workers utilizes more
sample and time, may not be precise in all the cases, and is a relatively broader classification system. The method of
indicating degree of hygroscopicity as per European Pharmacopoeia considers equilibration of sample for 24 hours
under single humidity condition and may not necessarily ensure equilibration in all the cases. Additionally, both
these methods do not provide information on solid state changes occurring within the sample during the course
of experiment. This research work envisages an efficient throughput method for hygroscopicity determination, and
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validates it with active and inactive pharmaceutical ingredients using sorption analysis. Further, this method has
been performed under optimal equilibration conditions, in a throughput manner (consuming less sample and time),
with additional information on solid state changes occurring within the experimental conditions. This throughput
method would be a valuable tool for hygroscopicity assessment of new chemical entities, during drug development
in particular, and across all pharmaceutical materials in general.
Keywords:  hygroscopicity, water vapor sorption, adsorption, desorption, pre-formulation

Introduction is often used for characterizing a material as such,[15] or


for making a selection among various polymorphs of a
The water-solid interaction(s) among pharmaceuticals drug molecule,[16–20] or for selecting salt-formers during
is of great interest in drug development process.[1–3] A initial salt screening attempts.[21–24] Based on its extent
pharmaceutically active or inactive ingredient encom- of interaction with water, a material can be classified as
passes varied levels of humidity during different stages non-hygroscopic or hygroscopic.
of product development, that is to say, during synthesis, Hygroscopicity of a sample can be determined by a
storage and analysis of that ingredient, or during various multitude of analytical methods.[25] The earliest reported
unit operations of drug product development like, spray and widely practiced method for hygroscopicity deter-
or freeze drying, wet milling, granulation, etc. The ad-/ mination or classification was the one proposed by
ab-sorption of water molecules by a pharmaceutical Callahan and co-workers.[26] This method is referred to as
solid can largely affect its performance with regard to the “conventional method” herein. It is based upon the
stability, flow, wetness, dissolution, compressibility or determination of EMC of samples equilibrated at partic-
compactability, etc.[4–13] Further, varied handling or stor- ular relative humidity (RH) using saturated salt solutions
age conditions can alter the properties of materials with in the well of the desiccators (Table 1).
regard to their equilibrium moisture content (EMC). This method for hygroscopicity classification of phar-
Hygroscopicity is a terminology commonly used for maceuticals is widely practiced as such,[27] or with some
describing the interaction of a material with water.[14] It modifications.[28] However, this method suffers from

Address for Correspondence:  Vaibhav Sihorkar, Pharmaceutical Development, Aurigene Discovery Technologies Limited, Bollaram Road,
Miyapur, Hyderabad, Andhra Pradesh 500 049, India. Tel: +91 40 4465 7777. Fax: +91 40 4465 7438. E-mail: vaibhav_s@aurigene.com;
IP Clearance No. H-01/1025/2010.
(Received 12 April 2011; revised 17 August 2011; accepted 18 August 2011)

348
Efficient throughput method for hygroscopicity  349

Table 1.  Hygroscopicity classification.


Conventional method European pharmacopoeia
Classification Criteria Classification Criteriaa
Non-hygroscopic Essentially no moisture increase below 90% RH; less than 20% (w/w) – –
increase in moisture content above 90% RH in 1 week
Slightly hygroscopic Essentially no moisture increase below 80% RH; less than 40% (w/w) Slightly hygroscopic Increase in mass
increase in moisture content above 80% RH in 1 week < 2% & ≥ 0.2%
Moderately hygroscopic Moisture content does not increase >5% (w/w) below 60% RH; less Hygroscopic Increase in mass
than 50% (w/w) increase in moisture content above 80% RH in 1 week < 15% & ≥ 2%
Very hygroscopic Moisture content will increase as low as 40–50% RH; greater than 20% Very hygroscopic Increase in
(w/w) increase in moisture content above 90% RH in 1 week mass ≥ 15%
a
Percent water uptake at 25°C/80% RH in 24 h.
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drawbacks such as time, sample and resource consum- analysis method[33] that could be obtained by using a
ing, tedious, and may offer chances of cross-contamina- sorption analyzer or dynamic vapor sorption (DVS)
tion. Moreover, any solid state changes occurring within instrument is proposed and validated in this paper. This
the sample during the course of the experiment can only method can serve as an efficient throughput method
be investigated by analyzing and comparing the starting for hygroscopicity determination or classification of
and end sample, using suitable analytical method(s). active and inactive pharmaceutical ingredients. It is a
European Pharmacopoeia (EP) also provides a method precise, accurate and robust method and utilizes less
for the determination of the tendency of a sample to take sample and time. It involves determination of weight
up atmospheric water. It has been cited as the method change for a sample purged with humid nitrogen under
for indicating the degree of hygroscopicity of a sample, isothermal conditions. These gravimetric observations
rather than its determination.[29] This method recom- could be made during increasing, as well as decreasing
mends determination of increase in mass of a sample humidity cycles, so as to capture the adsorption, as well
upon storage at 25°C and 80% RH for 24 hours (Table 1). as desorption isotherms of the sample, respectively. The
This however, subjects the sample to an environment shape, as well as any hysteresis in sorption isotherm
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with limited moisture for 24 hours. It may or may not can provide valuable information on the water-solid
necessarily yield the desired equilibration. interaction of the sample.[34] The equilibration time for
A comparison of results obtained from the data of water sorption in this method is much shorter than
both these methods may be difficult. This is because both that in desiccators, which are used in the conventional
the classification systems are sufficiently different. The methods. This is because of the small sample size and
results differ in the way the sample is exposed to mois- the continuous purge of gas to maintain a defined
ture and hence the classification. Additionally, these humidity level. Various research works cite the use of
criteria, which were originally directed toward inactive sorption analysis for hygroscopicity determination of
pharmaceutical ingredients, may not apply universally to samples.[35,36] However, this method has not yet been
different areas of drug development. validated using active and/or inactive pharmaceutical
A pharmaceutically active and inactive ingredient can ingredients. Nonetheless it generates enough confi-
exist in crystalline and amorphous form. Furthermore, dence to be used as a classification system.
within crystalline forms, anhydrous and hydrate forms A major advantage of this method could be its appli-
can also exist.[30] The hygroscopic nature of the sample cability to new chemical entities (NCEs) during regula-
would vary based upon the solid-state under analysis. tory submission of a new drug application. At the same
That is, in general amorphous and anhydrous crystal- time, it gives information about the solid-state changes
line forms of a compound tend to ad-/ab-sorb more occurring within the sample. The various mechanisms
moisture when compared with their respective crystal- by which solids interact with water,[34] and the important
line and hydrate forms.[31] Hence, it becomes important role played by the crystalline or amorphous form of the
to determine the hygroscopicity of the respective solid- solid could also get analyzed by using sorption method.
state sample during the hygroscopicity determination In the present study, the hygroscopicity of active and
experiment. Ensuring that the sample does not undergo inactive pharmaceutical ingredients was determined
any solid-state changes during the experiment is very using conventional, EP and sorption analysis method.
important,[32] so that the hygroscopicity classification The sorption method was assessed against the results
pertains to that particular solid-state of the compound obtained from conventional & EP method. A compara-
only and not of a different solid-state emerged after tive analysis was then drawn between the results from
moisture sorption. these methods. The solid state changes occurring in the
Hence, keeping in view the limitations of conven- sample during sorption analysis were also evaluated and
tional and EP method for hygroscopicity classifica- correlated. The envisaged work was aimed at validating
tion, we adopted another emerging methodology for sorption analysis as a potential tool to be used for hygro-
hygroscopicity determination. A water vapor sorption scopicity classification of samples.

© 2013 Informa Healthcare USA, Inc.


350  V. Murikipudi et al.

Materials and methods (100–300 mg) in open and tarred petri-plates. Then these
were placed inside labeled desiccators containing one
Materials of the saturated salt solutions (lithium chloride, potas-
The selection of active and inactive pharmaceutical sium carbonate, sodium chloride, potassium bromide
ingredients for the present study was made in order to and potassium nitrate for 11, 43, 75, 83 and 93%RH,
represent compounds varying in their hygroscopicity. respectively). After 7 days of storage at controlled room
They vary from low to high, as per the information avail- temperature (CRT, 25°C ± 2°C) and particular humidity,
able in literature. Further, the inactive pharmaceutical the samples were removed from the desiccators and the
ingredients were selected to represent commonly used decrease or increase in moisture was determined for
excipients used for preparing solid dosage forms. For each sample by obtaining the final equilibrium weight
example, diluents, disintegrants, binders, lubricants, gli- with the aid of a calibrated analytical balance.
dants, adsorbents, polymers, etc. Based upon these crite- The initial moisture content (A) of the samples was
ria, 30 inactive and 10 active pharmaceutical ingredients determined using thermo-gravimetric analysis (TGA),
were selected.
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Q5000 IR TGA (TA Instruments, USA). The samples


The 30 inactive pharmaceutical ingredients selected (5–15  mg) were analyzed under dry nitrogen purge
were; colloidal silicon dioxide (Aerosil 200), dicalcium (25 ml/min) in platinum crucibles at a heating rate of
phosphate anhydrous (A-Tab Granular), microcrystalline 10 °C/min from 25°C to 300°C. The percentage of weight
cellulose (Avicel PH 102), sodium salt of carboxymethyl loss corresponding to the first transition of the deriva-
cellulose (Blanose), carboxy vinyl polymer (Carbopol tive weight (%/°C) curve was integrated using Universal
914), cellulose acetate phthalate, dextrose (D-Glucose), Analysis 2000 software and considered as the initial
dicalcium phosphate dihydrate (Di-Tab Granular), moisture content of the sample.
cellulose ethyl ether (Ethyl cellulose), methyl prop-2- Initial moisture content of the sample was used to cal-
enoate (Eudragit RL PO), sodium carboxy methyl starch culate P (% dry basis), and EMC values were calculated
(Glycolys), sodium starch glycolate, hydroxypropyl from P with the aid of the equations 1 and 2. EMC values,
cellulose (Klucel LF), lactose anhydrous, lactose mono- at each RH tested, were tabulated, and samples were
hydrate, partially pregelatinized starch (Lycatab C), classified based upon the Callahan and co-workers’ clas-
magnesium aluminum silicate (Magnabrite), mag- sification system (Table 1).
For personal use only.

nesium carbonate anhydrous (Magnesium carbon-


ate), magnesium oxide heavy, magnesium stearate, [(W . A/100) – B] . 100
P= (1)
D-mannitol (Pearlitol), polyethylene glycol-8000 (PEG- W - [W . A/100]
8000), hydroxypropyl methylcellulose (Pharmacoat
606), polyvinyl pyrrolidone (Plasdone K-30), polyoxy- P
ethylene-propylene block copolymer (Poloxamer-188), EMC = (2)
P + 100
cross-linked polyvinyl pyrrolidone (Polyplasdone
XL-10), sodium stearyl fumarate, corn starch, silicon
Where, P % moisture dry basis
dioxide (Syloid) and lastly talc. The 10 active pharma-
W initial sample weight in grams
ceutical ingredients selected were Albendazole, Aspirin,
A % moisture at start
Enalaprilat, Famotidine, Irbesartan, Metoprolol suc-
B Weight change at equilibrium in grams
cinate, Naproxen sodium, Niacin, Nimesulide and
EMC Equilibrium moisture content
Raloxifene hydrochloride.
All inactive and active pharmaceutical ingredients
used under this study were procured from certified com- Hygroscopicity assessment by European
mercial sources. Additionally, as per the information pharmacopoeia method
provided in their certificate of analysis, it was ascertained The hygroscopicity data was generated using the method
that their residual organic solvent content was minimal reported in European Pharmacopoeia.[29] In brief, an
(within ICH limits), and all volatile losses were due to excess amount of saturated salt solution (with excess
moisture present. crystals) of ammonium chloride was placed in the well
of the desiccators. The humidity and temperature were
Hygroscopicity assessment by conventional checked using a calibrated thermo-hygrometer. Samples
method of each material (100–300 mg) were weighed into open
and tarred plastic petri-plates and then placed into a
The hygroscopicity data was generated using the method desiccator, which was labeled and maintained at CRT
reported by Callahan and co-workers.[26] In brief, an and 80 ± 2%RH. After 24 hours of storage, the samples
excess amount of saturated salt solution (with excess were removed from the desiccator, and the final mass of
crystals) was placed in the well of the desiccators, and each sample was determined with the aid of a calibrated
the humidity and temperature were checked using a cali- analytical balance.
brated thermo-hygrometer. The EMC was determined The percentage of increase in mass of each sample
by placing accurately weighed samples of each material was calculated using equation 3, and the samples were

 Pharmaceutical Development and Technology


Efficient throughput method for hygroscopicity  351
classified for their hygroscopic nature as per the EP clas- (Table 3) pharmaceutical ingredients. This was done
sification system (Table 1). to ensure the reproducibility of classification (as given
by Callahan and co-workers) under experimental set-
m3 - m2 100 up used. Most of the excipients could be classified as
Percentage of increase in Mass = (3)
m2 - m1 reported in literature,[26] except for a few.
Classification of samples under each class by conven-
Where,
tional method relies on EMC data generated at two RH
m1 mass of empty Petri plate 
values. Due to this, it is difficult at times to fit a particular
m2 mass of Petri plate and sample (Initial)
sample under both criteria, as it may satisfy more than
m3 mass of Petri plate and sample (after 24 h)
one criterion of classification. It may lead to an overlap
Hygroscopicity assessment by sorption analysis of hygroscopicity class for the same sample and potential
method exists to add subjectivity to the hygroscopicity class of the
This involved subjecting the sample to water vapor sample selected in some cases.
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sorption analysis using Q5000 SA sorption analyzer (TA For e.g. Metoprolol succinate and Niacin could be
Instruments, USA) at 25°C. Vapor from the samples were classified as slightly hygroscopic (refer to the classifica-
subjected to varying conditions of humidity under iso- tion mentioned in Table 1). Moisture increase below 80%
thermal conditions, and the responses were measured RH is minimal (since the term “minimal” is not defined,
gravimetrically. To avoid the possibility of change in the and covers broadly up to 10%, values of 2.87% and 3.19%
solid state of the sample, initial drying of the sample EMC are herein considered as minimal at 75% RH for
within the sorption analyzer was not performed. All the Metoprolol succinate and Niacin, respectively). Also, the
samples were then analyzed “as is” from 25°C and 40% moisture increase above 80% RH is less than 40% (5.77%
RH. Around 5–15 mg sample was exposed to increasing and 5.81% EMC at 93% RH for Metoprolol succinate and
environmental humidity from 40%RH to 90%RH. The step Niacin, respectively). The same data, however, quali-
equilibrium criterion was set as 0.1% w/w in 10 min with fies them for moderately hygroscopic as well, because
a maximum step time of 60 min. The samples were then increase in moisture content below 60% RH is less than
subjected to desorption from 90% RH to 0% RH. The step 5% (1.80% and 1.30% EMC at 43% RH for Metoprolol
succinate and Niacin, respectively) and above 80% RH,
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equilibrium criterion for desorption was the same as that


of adsorption. The adsorption-desorption was repeated it is less than 50% (5.77% and 5.81% EMC at 93% RH for
for one more cycle from 0%RH to 90%RH to 0%RH. The Metoprolol succinate and Niacin, respectively).
percentge of weight change at 25°C and 80% RH in the first Similarly, Enalaprilat and Naproxen sodium could
adsorption cycle (measurement criterion analogous to be classified as moderately hygroscopic, because, above
that mentioned in EP) was calculated as per equation 4. 80% RH, increase in moisture content is less than 50%
(9.53% and 24.48% EMC at 93% RH for Enalaprilat and
W2 + W1 Naproxen sodium, respectively). Though, below 60% RH
% Weight Change = × 100 (4)
W1 the increase in moisture content is more than 5% (5.95%
 Where, and 12.30% EMC at 43% RH for Enalaprilat and Naproxen
sodium, respectively). The same data still qualifies them
W1 weight of sample at the start of the experiment as very hygroscopic, as well as increase in moisture con-
W2 weight of sample in equilibrium at 25°C and 80% RH tent is low at 40–50% RH (5.95% and 12.30% EMC at 43%
The presence of hysteresis between the adsorption RH for Enalaprilat and Naproxen sodium, respectively)
and desorption profiles was used to interpret the sample and more than 20% above 90% RH for Naproxen sodium
characteristics. This was in terms of solid state changes (24.48% EMC at 93% RH). The same is the case with some
occurring under the experimental conditions of hygro- of the inactive pharmaceutical ingredients, like Aerosil,
scopicity determination within the sorption analyzer. To which can be classified as non-hygroscopic or slightly
cross check the interpretations drawn from the sorption hygroscopic. Avicel PH 102, cellulose acetate phthalate,
isotherm, all the samples were analyzed by powder X- ray D-Glucose, Eudragit RL PO, Magnesium carbonate and
diffractometry (PXRD) before and after performing sorp- Magnesium oxide can be classified as slightly or moder-
tion analysis. PXRD of the samples was performed using ately hygroscopic. Similarly PEG 8000, Lycatab C, Starch
a Rigaku 2200 diffractometer (Rigaku, Japan) equipped and Syloid come under very hygroscopic classification.
with a Cu K∝1/50kV/34mA X-Ray source. The X-rays were Similar observations can also be seen with the original
received by a scintillation detector. All diffraction patterns work of Callahan and co-workers.[26] These results indi-
were collected in continuous mode at a scan speed of cate that the conventional method of hygroscopicity clas-
3°/min with a scan step of 0.02° over range of 3–45 °2θ. sification is relatively broad and overlapping.
Unlike conventional method, no historical data could
be traced for hygroscopicity classification of selected
Results and discussion samples by EP method. The results of hygroscopicity
Conventional method of hygroscopicity determination classification of 30 inactive and 10 active pharmaceuti-
was used to classify 30 inactive (Table 2) and 10 active cal ingredients determined by EP method are compiled

© 2013 Informa Healthcare USA, Inc.


352  V. Murikipudi et al.

Table 2.  Hygroscopicity classification of inactive pharmaceutical ingredients studied by conventional method.
EMC (%) values at 25°C & different RH
S. No. Inactive pharmaceutical ingredient 11% 43% 75% 83% 93% Hygroscopicity classa
1 Aerosil –1.23 0.20 3.38 6.97 15.36 NHb
2 A-tab granular 0.42 1.09 1.28 1.34 3.27 NH
3 Di-tab granular –0.16 0.01 1.08 1.33 2.14 NH
4 Ethyl cellulose –5.49 –0.83 –0.82 0.24 4.24 NH
5 Lactose anhydrous –32.2 0.72 0.9 1.38 2.85 NH
6 Lactose monohydrate –3.03 –0.26 0.65 2.09 3.32 NH
7 Magnesium stearate –0.8 0.02 0.95 1.79 2.56 NH
8 Pearlitol –0.55 0.27 1.12 1.55 3.26 NH
9 Sodium stearyl fumarate –1.22 –0.32 1.11 1.69 3.21 NH
10 Talc –0.57 0.65 1.06 1.64 2.25 NH
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11 Avicel PH 102 2.46 7.35 9.66 10.46 14.90 SHc


12 Cellulose acetate phthalate –3.14 –2.28 3.08 3.54 9.11 SHc
13 D–glucose –0.38 2.45 3.62 9.84 55.65 SHc
14 Eudragit RL PO –0.09 2.01 4.73 7.34 11.04 SHc
15 Magnesium carbonate –4.84 1.11 2.36 3.72 6.28 SHc
16 Magnesium oxide 1.85 2.61 5.33 6.80 9.28 SHc
17 PEG 8000 –3.43 –0.05 1.52 2.74 51.07 SHd
18 Poloxamer 188 –0.42 0.13 1.25 2.66 42.3 SHc
19 Klucel LF –2.2 3.38 6.64 9.35 19.12 MH
20 Lycatab C 6.67 9.47 12.90 13.04 21.15 MHd
21 Magnabrite 2.07 5.96 13.46 16.37 20.84 MHd
22 Pharmacoat 606 2.04 2.95 9.03 12.75 21.29 MH
23 Starch 3.50 9.85 12.45 13.43 18.35 MHd
24 Syloid –1.27 9.02 12.86 14.3 16.14 MHd
For personal use only.

25 Blanose 11.13 15.71 26.73 29.05 49.25 VH


26 Carbopol 914 2.43 5.63 16.66 24.84 37.24 VH
27 Glycolys 5.36 9.21 21.22 30.91 47.25 VH
28 Plasdone K-30 9.52 14.24 25.93 27.41 41.25 VH
29 Polyplasdone XL-10 0.85 16.16 20.32 24.46 33.35 VH
30 Sodium starch glycolate 6.93 18.35 23.07 27.75 44.75 VH
a
NH− Non-hygroscopic, SH− Slightly hygroscopic, MH− Moderately hygroscopic, VH− Very hygroscopic.
Samples can also be classified as bslightly hygroscopic, cmoderately hygroscopic & dvery hygroscopic.

Table 3.  Hygroscopicity classification of active pharmaceutical ingredients studied by conventional method.
EMC (%) values at 25°C & different RH

S. No. Active pharmaceutical ingredient 11% 43% 75% 83% 93% Hygroscopicity classa
1 Albendazole –0.28 0.31 1.54 1.92 3.54 NH
2 Aspirin –0.73 0.29 1.05 1.77 3.08 NH
3 Famotidine –0.47 0.82 1.85 2.83 3.94 NH
4 Irbesartan –0.84 0.29 1.94 2.58 3.83 NH
5 Nimesulide –0.47 0.23 1.38 1.65 3.19 NH
6 Raloxifene hydrochloride –0.46 0.46 1.18 2.02 3.08 NH
7 Metoprolol succinate –1.67 1.80 2.87 4.90 5.77 SHb
8 Niacin –0.97 1.30 3.19 4.84 5.81 SHb
9 Enalaprilat –0.29 5.95 7.64 7.65 9.53 MHc
10 Naproxen sodium 5.04 12.30 14.14 18.64 24.48 MHc
a
NH− Non-hygroscopic, SH− Slightly hygroscopic, MH− Moderately hygroscopic, VH− Very hygroscopic.
Samples can also be classified as bmoderately hygroscopic & cvery hygroscopic.

in Tables 4 and 5, respectively. These results do not cor- the percentage of increase in mass occurring on storage
relate well with that of the conventional method. This at 25°C and 80% RH for 24 h, and neither has it included
might be due to the short equilibration time of 24 hours the initial moisture content, nor the EMC of sample for
at single RH condition applied in the EP method, as its classification, unlike that of the conventional method.
compared to that of 7 days at each RH condition in con- The results may therefore, rely heavily on the thermal his-
ventional method. Moreover, EP method only considers tory of the starting material, and there lies a potential for

 Pharmaceutical Development and Technology


Efficient throughput method for hygroscopicity  353

Table 4.  Hygroscopicity classification of inactive pharmaceutical Table 5.  Hygroscopicity classification of active pharmaceutical
ingredients studied by EP method. ingredients studied by EP method.
Inactive pharmaceutical % Increase Hygroscopicity Active pharmaceutical % Increase Hygroscopicity
S. No. ingredient in mass classa S. No. ingredient in mass classa
1 Aerosil –1.64 Not defined in EP 1 Albendazole 0.10 Not defined in EP
2 A-tab granular –1.68 Not defined in EP 2 Aspirin –0.03 Not defined in EP
3 D-glucose –0.23 Not defined in EP 3 Enalaprilat –0.08 Not defined in EP
4 Di-tab granular –0.07 Not defined in EP 4 Famotidine –0.31 Not defined in EP
5 Ethyl cellulose 0.15 Not defined in EP 5 Raloxifene hydrochloride 0.15 Not defined in EP
6 Lactose anhydrous –0.51 Not defined in EP 6 Irbesartan 0.24 SH
7 Lactose monohydrate –0.21 Not defined in EP 7 Metoprolol succinate 0.59 SH
8 Magnesium carbonate –1.10 Not defined in EP 8 Naproxen sodium 0.59 SH
9 Pearlitol 0.15 Not defined in EP 9 Niacin 1.37 SH
10 Talc 0.09 Not defined in EP 10 Nimesulide 0.30 SH
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11 Cellulose acetate 1.50 SH a


SH − Slightly hygroscopic.
phthalate
12 Eudragit RL PO 0.66 SH Table 6.  Hygroscopicity classification criterion by sorption
13 Lycatab C 0.52 SH analysis.
14 Magnesium oxide 0.35 SH Hygroscopicity class Criteriaa
15 Magnesium stearate 0.49 SH Non-hygroscopic < 0.2% (w/w)
16 PEG− 8000 0.21 SH Slightly hygroscopic 0.2–2% (w/w)
17 Pharmacoat 606 1.77 SH Hygroscopic / Moderately hygroscopic 2–15% (w/w)
18 Poloxamer-188 0.17 SH Very hygroscopic >15% (w/w)
19 Sodium stearyl fumarate 0.29 SH a
Percent water uptake at 25°C/80% RH in first adsorption cycle of
20 Avicel PH 102 3.26 H sorption isotherm
21 Blanose 6.15 H
22 Carbopol 914 9.27 H and initiating sorption analysis from ambient conditions,
For personal use only.

23 Glycolys 11.10 H i.e. 25°C and 40% RH) after attaining equilibration in
24 Klucel LF 5.19 H weight over the step equilibrium. The reasons for such an
25 Magnabrite 3.65 H approach were manifold. Foremost being its synchroni-
26 Plasdone K-30 5.87 H zation with the criterion of EP and conventional method.
27 Polyplasdone XL-10 6.03 H Callahan and co-workers (referred herein as conventional
28 Sodium starch glycolate 11.96 H method) utilized the percentage of moisture increase in
29 Starch 2.18 H sample mostly on exposure to high humidity conditions,
30 Syloid 2.69 H such as 80 and 90% RH. However, samples may behave dif-
a
SH − Slightly hygroscopic, H − Hygroscopic. ferently at times under different RH conditions. Therefore,
some samples may get unambiguously classified under
a material being classified at different degrees of hygro- more than one classification, as described elsewhere in
scopicity under differ experimental backgrounds. this manuscript. Further, hygroscopicity classification
The proposed efficient throughput method was used by sorption analysis has added advantage of sample and
to classify hygroscopicity class of 30 inactive and 10 active time conservation, along with the complete view of sorp-
pharmaceutical ingredients, and results were compared tion profile of “as is” (from I adsorption-desorption cycles)
with the data of hygroscopicity generated using conven- and desorbed (from II adsorption-desorption cycles)
tional and EP methods. The basis for validating water sample. Furthermore, this also provides with an addi-
sorption analysis as a potential tool for hygroscopicity tional information on potential solid-state transformation
classification was to attain moisture equilibration of the due to moisture sorption or desorption (hysteresis and/
sample with the most efficient mechanism with less time or hydrate formation potential during adsorption and
and compound. Additionally, to make unequivocal and desorption cycles) for any further investigation. However,
unambiguous hygroscopicity classification of compounds it is up to the discretion of experimenter to modify the
based on equilibrium moisture reached at an optimally temperature or humidity conditions for sample analysis
selected RH condition. The premise of the strategy in the by sorption analyzer. The experimenter can then evalu-
envisaged work toward validating a novel throughput ate the obtained data for arriving at logical conclusion
method of hygroscopicity classification, relied upon equil- to characterize drug and support drug product develop-
ibration concept of conventional method and an optimal ment. The authors also feel it is worth to maintain the
RH concept (and classification theme) of EP method. classification of samples as “Non-Hygroscopic” as in
The criterion for hygroscopicity classification by sorp- conventional method. The hygroscopicity classification
tion analysis has been taken as the EMC of the sample at system followed under envisaged work is detailed in Table
25°C and 80% RH. It is defined as the percentage of weight 6, and is derived for 30 inactive and 10 active pharmaceu-
change of “as is” sample (without pre-drying of sample tical ingredients listed in Tables 7 and 8, respectively.
© 2013 Informa Healthcare USA, Inc.
354  V. Murikipudi et al.

Table 7.  Hygroscopicity classification of inactive pharmaceutical


ingredients studied by sorption analysis.
% Weight
Inactive pharmaceutical change Hygroscopicity
S. No. ingredient (25°C/80%RH) classa
1 D-glucose 0.15 NH
2 Di-tab granular 0.04 NH
3 Lactose anhydrous 0.06 NH
4 Lactose monohydrate 0.03 NH
5 Magnesium stearate 0.18 NH
6 Pearlitol 0.12 NH
7 Sodium stearyl fumarate 0.01 NH
8 Talc 0.06 NH
9 A-tab granular 0.47 SH
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10 Ethyl cellulose 1.72 SH


11 Eudragit RL PO 1.92 SH
12 Magnesium carbonate 0.46 SH
13 Magnesium oxide 0.57 SH
14 PEG - 8000 0.68 SH
15 Aerosil 3.58 H/MH
16 Avicel PH 102 6.08 H/MH
17 Carbopol 914 9.14 H/MH
18 Cellulose acetate phthalate 5.33 H/MH
19 Klucel LF 8.91 H/MH
20 Lycatab C 5.49 H/MH
21 Magnabrite 7.62 H/MH
22 Pharmacoat 606 10.43 H/MH
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23 Poloxamer-188 10.95 H/MH


24 Starch 7.95 H/MH
25 Syloid 4.01 H/MH
26 Blanose 23.72 VH
27 Glycolys 15.07 VH
28 Plasdone K-30 24.47 VH
29 Polyplasdone XL-10 19.23 VH
30 Sodium starch glycolate 22.66 VH Figure 1. Comparison of hygroscopicity classification of (a)
a
NH − Non-hygroscopic, SH − Slightly hygroscopic, H − Hygroscopic, inactive and (b) active pharmaceutical ingredients by different
MH − Moderately hygroscopic, VH − Very hygroscopic. methods. Key: NH–Non-hygroscopic, SH–Slightly hygroscopic,
MH–Moderately hygroscopic, H–Hygroscopic, VH–Very
Table 8.  Hygroscopicity classification of active pharmaceutical hygroscopic. * Criteria for “Non-Hygroscopic” materials not
ingredients studied by sorption analysis. defined in EP method of hygroscopicity classification.
% Weight
Active pharmaceutical change Hygroscopicity with those of conventional method. Additionally, both
S. No. ingredient (25°C/80%RH) classa these methods provide sufficient equilibration of sam-
1 Albendazole 0.011 NH ples under a specific humidity condition, although the
2 Aspirin 0.002 NH equilibration time and mechanisms are different. On
3 Famotidine 0.004 NH the other hand, EP method could probably have under-
4 Metoprolol succinate 0.006 NH evaluated the samples being either just “Hygroscopic”
5 Niacin 0.016 NH or “Slightly Hygroscopic”. Even though they could have
6 Nimesulide 0.002 NH been classified one level up into “Very Hygroscopic” or
7 Raloxifene hydrochloride 0.018 NH “Hygroscopic” class by other two methods. This suggests
8 Irbesartan 0.341 SH toward a potentially incomplete bulk equilibration of
9 Enalaprilat 1.679 SH samples within the timeframe of EP method, i.e. 24 h. On
10 Naproxen sodium 3.111 H/MH the contrary, an equivalent equilibration to that seen in
a
NH − Non-hygroscopic, SH − Slightly hygroscopic, H − Hygroscopic, conventional method could be achieved with sorption
MH − Moderately hygroscopic.
analysis despite the use of lesser amount of sample and
A comparative analysis of hygroscopicity classification lesser but adequate equilibration time due to highly effi-
of inactive and active pharmaceutical ingredients inves- cient contact of sample with water vapor in a micro-envi-
tigated under present study by different methodologies ronment of interaction chamber. The evident differences
is presented in Figure 1. An overview of the data suggests of classifying 30 inactive and 10 active pharmaceutical
that results of sorption analysis are in better correlation ingredients (Figure 1) using sorption could be attributed
 Pharmaceutical Development and Technology
Efficient throughput method for hygroscopicity  355
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Figure 2.  Results of (i) sorption analysis and (ii) PXRD of Naproxen sodium (i) before and (ii) after sorption analysis.

to a hybrid approach of envisaged method, which clas- pharmaceutical ingredients showed none or minimal
sifies the compounds on EP criterion despite ensuring hysteresis in sorption isotherms. This was with further
equilibration as per conventional method. complimented with no solid-state transformation as
The percentage of weight change determined for clas- determined by PXRD analysis, before and after sorp-
sifying the hygroscopic nature of the sample under sorp- tion analysis (data not shown). Majority of the active
tion conditions can be considered as EMC of the sample pharmaceutical ingredients also showed minimal or no
at that particular temperature and humidity. Moreover, hysteresis in sorption isotherms, except for Enalaprilat
hygroscopicity classification by sorption analysis is fur- and Naproxen sodium. These samples were further
ther beneficial in terms of exposure of sample to increas- investigated for solid-state changes and were found to
ing RH with equilibration at each RH step. This however, be transforming into alternate solid-state during sorp-
is not the case with conventional and EP method wherein tion analysis (Figures 2 and 3). This has been a critical
the sample is being subjected to a fixed RH at a time. evaluation that can remain unaddressed if conven-
An important aspect of envisaging a through- tional, or EP methods are being used.
put method for hygroscopicity classification was to The conventional method of hygroscopicity classifica-
simultaneously generate pivotal information that tion utilizes 1–2 gm of sample for all RH conditions and
could serve as a means to understand the behavior it takes 7 days for completion. The EP method of hygro-
of materials under moisture ingress. All the inactive scopicity classification on the other hand utilizes lesser
© 2013 Informa Healthcare USA, Inc.
356  V. Murikipudi et al.
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For personal use only.

Figure 3.  Results of (i) sorption analysis and (ii) PXRD of Enalaprilat (i) before and (ii) after sorption analysis.

sample (100–300 mg) and lesser time (1 day), but it has its EP and sorption analysis method. Conventional method
own shortcomings, as elaborated earlier. Determination of hygroscopicity classification utilizes more time, sam-
of hygroscopicity by sorption analysis requires 10–20 mg ple, and does not provide any insight on the solid state
of sample, and complete information could be captured changes occurring within the sample under the experi-
within 1–2 days across all RH values. In brief, the sorption mental conditions of analysis. A sample can convert from
analysis saves lot of time, consumes lesser samples and anhydrous to hydrate state at high RH, and vice versa
provides more technical inputs from a single experiment, at low RH conditions, chances do exists in the conven-
which can lead to a logical conclusion for classification tional method and the starting material may undergo
of hygroscopicity of active and inactive pharmaceuti- polymorph change during the experiment. In this sce-
cal ingredients when compared to that of conventional nario, no information would be available whether the
method. classification provided is of the starting polymorph or
the new polymorph of the sample by conventional or EP
methods. Moreover, the classification provided by con-
Conclusion ventional method is very broad and overlapping, so that
Hygroscopic nature of 30 inactive and 10 active pharma- same sample can be classified under two categories if the
ceutical ingredients was determined using conventional, data is interpreted by two different personnel.
 Pharmaceutical Development and Technology
Efficient throughput method for hygroscopicity  357
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AAPS PharmSciTech 2005;6:E115–E119.
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