479
14 Quantitative Structure-Property Relationship Analysis …
14.4.1.2 Investigation of Permeability and Solubility of Drugs on the WHO
List Using SiRMS Approach
Creation of in silico BCS to study the relationship between the structure of APIs
and their bioavailability is highly important. Similarly to permeability classification, this would be based on experimental human intestine permeability data, or
well-defined mass balance studies and/or comparison to an intravenous reference
dose. However, since such data are available only for a small number of drugs, the
provisional permeability classification was based on correlation of the estimated
n-octanol/water partition coefficient using both MlogP and ClogP of the uncharged
form of the drug molecule [63, 64]. In order to determine the broad applicability and significance of the BCS, we developed a provisional classification of the
WHO Essential Medicines List [65] and then extended this analysis to the top 200
drugs on the United States and others country lists [66]. Values for drug solubility
were obtained from standard references (e.g., Merck Index, USP, etc.). The BCS
classification of the WHO medicines was conducted using two criteria. The first,
a solubility classification, was based on the calculated dose number. Drugs were
categorized as “soluble” if they had a dose number of 1. The finding that 67 % of
the drugs on the WHO list and 68 % on the top 200 U.S. list were classified as “high
solubility” drugs suggests that major differences in drug BCS classification of the
two lists are unlikely. A total of 43 drugs on the WHO list and 49 drugs on the U.S.
list exhibited a solubility of < 0.1 mg/ml. However, a few of these drugs were classified as “soluble” drugs on the basis of dose numbers and may reflect recent trends
toward development of highly lipophilic, low-solubility drugs that are quite potent.
The percentages of the drugs in IR dosage forms on the WHO list that were classified as class 1 drugs based on Mlog P or Clog P were 23.6 and 28.5 %, respectively.
The corresponding percentage of drugs classified as class 3 drugs were 31.7 and
35.0 %, respectively, and regulatory approval of biowaiver for this class of drugs is
scientifically justified and recommended by WHO [67]. Hence, the majority of IR
oral drug products on the WHO List of Essential Drugs are candidates for waiver
of in vivo BE testing based on an in vitro dissolution test. The impact of waiving an
expensive in vivo BE testing and its replacement by rapid and affordable in vitro
dissolution standards in developing countries is expected to be profoundly significant. Similar results were obtained in a subsequent classification of the WHO list
of Essential Medicines that was based primarily on human fraction absorbed ( F abs )
literature data for the permeability assignment [49]. Out of 61 drugs that could be
reliably classified, 34 % were classified as class I, 17 % as class II, 39 % as class III,
and 10 % as class IV. In this analysis, hence, more than 70 % of the classified drugs
proved to be candidates for waiver of in vivo BE testing based on in vitro dissolution
test. Of course, other drug product characteristics, such as the therapeutic index and
the potential influence of the excipients on the rate and extent of absorption, should
also be considered.
In our studies, we have used the following drugs relating to different classes of
BCS. SiRMS approach was used to develop the models that can classify compounds
14 Quantitative Structure-Property Relationship Analysis …
14.4.1.2 Investigation of Permeability and Solubility of Drugs on the WHO
List Using SiRMS Approach
Creation of in silico BCS to study the relationship between the structure of APIs
and their bioavailability is highly important. Similarly to permeability classification, this would be based on experimental human intestine permeability data, or
well-defined mass balance studies and/or comparison to an intravenous reference
dose. However, since such data are available only for a small number of drugs, the
provisional permeability classification was based on correlation of the estimated
n-octanol/water partition coefficient using both MlogP and ClogP of the uncharged
form of the drug molecule [63, 64]. In order to determine the broad applicability and significance of the BCS, we developed a provisional classification of the
WHO Essential Medicines List [65] and then extended this analysis to the top 200
drugs on the United States and others country lists [66]. Values for drug solubility
were obtained from standard references (e.g., Merck Index, USP, etc.). The BCS
classification of the WHO medicines was conducted using two criteria. The first,
a solubility classification, was based on the calculated dose number. Drugs were
categorized as “soluble” if they had a dose number of 1. The finding that 67 % of
the drugs on the WHO list and 68 % on the top 200 U.S. list were classified as “high
solubility” drugs suggests that major differences in drug BCS classification of the
two lists are unlikely. A total of 43 drugs on the WHO list and 49 drugs on the U.S.
list exhibited a solubility of < 0.1 mg/ml. However, a few of these drugs were classified as “soluble” drugs on the basis of dose numbers and may reflect recent trends
toward development of highly lipophilic, low-solubility drugs that are quite potent.
The percentages of the drugs in IR dosage forms on the WHO list that were classified as class 1 drugs based on Mlog P or Clog P were 23.6 and 28.5 %, respectively.
The corresponding percentage of drugs classified as class 3 drugs were 31.7 and
35.0 %, respectively, and regulatory approval of biowaiver for this class of drugs is
scientifically justified and recommended by WHO [67]. Hence, the majority of IR
oral drug products on the WHO List of Essential Drugs are candidates for waiver
of in vivo BE testing based on an in vitro dissolution test. The impact of waiving an
expensive in vivo BE testing and its replacement by rapid and affordable in vitro
dissolution standards in developing countries is expected to be profoundly significant. Similar results were obtained in a subsequent classification of the WHO list
of Essential Medicines that was based primarily on human fraction absorbed ( F abs )
literature data for the permeability assignment [49]. Out of 61 drugs that could be
reliably classified, 34 % were classified as class I, 17 % as class II, 39 % as class III,
and 10 % as class IV. In this analysis, hence, more than 70 % of the classified drugs
proved to be candidates for waiver of in vivo BE testing based on in vitro dissolution
test. Of course, other drug product characteristics, such as the therapeutic index and
the potential influence of the excipients on the rate and extent of absorption, should
also be considered.
In our studies, we have used the following drugs relating to different classes of
BCS. SiRMS approach was used to develop the models that can classify compounds