RU CMC Section for Metopimazine Essay

Final Project. Students will write the CMC section for a clinical trial application (CTA or IND) for Phase 1 study for metopazime in the US. Write the CMC sections for drug substance and drug product sections for three formulations. Instructions and information to support the authoring have been provided in the readings, instructions, and the lecture.  

See the Final Project Instructions handout provided in this Week’s Module for the rubric and additional information regarding this assignment. Also, see the readings provided in this Week’s Module for further information.CHEM07493 – Final Project Rubric

Final Project
There are two MDDs mentioned in the final project: 50 mg/day and 100 mg/day. This was a
typo.
Please use 100 mg/day MDD for all your calculations, specifications and project. I have
provided an example of the IND as a reading. You will need to provide a similar IND for your
final project. However, I have removed a few sections form the requirement. Please ONLY
provide the sections listed in the checklist below.
1. You need to provide the information listed in slides 10 and 14 of lecture 21. The chemistry
manufacturing and controls section only is what I want – not any other sections. The
section details required is presented below as a checklist. I will use the list provided below as
a checklist. If you miss something in this list it will be automatically deduct points.
2. You do no need to provide an IB for this final project. You need to provide the CMC section
of an IND.
3. You have to assume a Phase 1 study. The reason I say this is because the level of detail and
the specifications will be catered for Phase 1 study. Please use the information I provide in
the lecture as a guide.
4. On slide 11 – I provide the two formulations I want you to use.
5. The reference standard would discuss the purity of the reference standard and the batch being
used. So you would include the data for the reference std provided.
6. Composition section will discuss the amount/type/role/quality std of each excipient added to
the active ingredient (drug substance). Formulation section would discuss the actual
formulation (whether its tablet or injectable) and its route of administration. If its injectable it
would discuss how it will be administered in the patient. Eg whether it needs to be diluted or
not – using IV bags or syringes etc.
7. The manufacturing process describes the synthesis of the drug substance in the drug
substance sections (Sections S) or how the active was formulated to make capsules or
solution for injection in the drug product section (Sections P).
8. Control of materials briefly describes the starting materials used to manufacture the active
drug substance and their vendor and purity information.
9. When you don’t have the information – eg Manufacturer, reference standard – then just make
it up and let me know about it (as a foot note or ref note).
10. A lot of the information you are looking for below is provided in the literature paper I
provided as a reading. For instance characterization (NMR, MS) is in the literature paper.
Impurities and batch data information was provided in the lecture.
11. Control of drug product includes the specifications for drug product and justification for
specs. This is similar to assignment 4 you did. Difference is assignment 4 was for drug
substance (which you will include in drug substance sections) and this will be specifications
for drug product. We have discussed the differences for oral versus parenteral drug product
formulations in the lectures. For both drug substance and drug product sections you will need
to provide a justification of each test using data and calculations in the justification of
specification section.
12. The final project lecture indicates the formulations you need to discuss. You need to provide
a generic manufacturing process for the capsules and solution for injection in the drug
product manufacturing process sections.
You will be using the route provided in the Metopimazine paper (provided as a reading) as your
manufacturing process to make the drug substance. The paper at the end in the experimental
section also provides details about the characterization regarding NMR etc.
CHECKLIST FINAL PROJECT
Section 3.2.S DRUG SUBSTANCE
☐3.2.S.1 General Information
☐3.2.S.1.1 Nomenclature
☐3.2.S.1.2 Structure
☐3.2.S.1.3 General Properties
☐3.2.S.2.1 Manufacturer
☐3.2.S.2.2 Description of Manufacturing Process and Process Controls
☐3.2.S.2.3 Control of Starting Materials
☐3.2.S.3 Characterization
☐3.2.S.3.1 Elucidation of Structure and Other Characteristics
☐3.2.S.3.2 Impurities
☐3.2.S.4 Control of Drug Substance
☐3.2.S.4.1 Specification
☐3.2.S.4.2 Analytical Procedures
☐3.2.S.4.4 Batch Analyses
☐3.2.S.4.5 Justification of Specification
☐3.2.S.5 Reference Standards or Materials
☐3.2.S.6 Container Closure Systems
☐3.2.S.7 Stability
3.2.P DRUG PRODUCT – Formulation 1
☐3.2.P.1 Description and Composition of
the Drug Product
☐3.2.P.2 Pharmaceutical Development
☐3.2.P.3.1 Manufacturer
☐3.2.P.3.2 Batch Formula
☐3.2.P.3.3 Description of Manufacturing
Process and Process Controls
☐3.2.P.4 Control of Excipients
☐3.2.P.4.5 Excipients of Human or Animal
Origin
☐3.2.P.4.6 Novel Excipients
☐3.2.P.5 Control of Drug Product
☐3.2.P.5.1 Specification
☐3.2.P.5.2 Analytical Procedures
☐3.2.P.5.4 Batch Analyses
☐3.2.P.5.5 Characterization of Impurities
☐3.2.P.5.6 Justification of Specification
☐3.2.P.6 Reference Standards or Materials
☐3.2.P.7 Container Closure Systems
☐3.2.P.8 Stability
3.2.P DRUG PRODUCT – Formulation 2
☐3.2.P.1 Description and Composition of
the Drug Product
☐3.2.P.2 Pharmaceutical Development
☐3.2.P.3.1 Manufacturer
☐3.2.P.3.2 Batch Formula
☐3.2.P.3.3 Description of Manufacturing
Process and Process Controls
☐3.2.P.3.4 Controls of Critical Steps and
Intermediates
☐3.2.P.4 Control of Excipients
☐3.2.P.4.5 Excipients of Human or Animal
Origin
☐3.2.P.4.6 Novel Excipients
☐3.2.P.5 Control of Drug Product
☐3.2.P.5.1 Specification
☐3.2.P.5.2 Analytical Procedures
☐3.2.P.5.4 Batch Analyses
☐3.2.P.5.5 Characterization of Impurities
☐3.2.P.5.6 Justification of Specification
☐3.2.P.6 Reference Standards or Materials
☐3.2.P.7 Container Closure Systems
☐3.2.P.8 Stability
Rubric to be used for grading: Out of 130 points
Criteria
Checklist for
Drug substance
Manufacturing
Section
Specifications
Justification of
Specifications
Checklist for
Formulation 1
Manufacturing
Section
Specifications
Does not meet
expectations (0)
Does not meet
expectations (0)
Does not meet
expectations (0)
Does not meet
expectations (0)
Does not meet
expectations (0)
Justification of
Specifications
Checklist for
Formulation 2
Does not meet
expectations (0)
Does not meet
expectations (0)
Does not meet
expectations (0)
Does not meet
expectations (0)
Manufacturing
Section
Does not meet
expectations (0)
Ratings (points)
Meets some
expectations
(10)
Meets some
expectations (2)
Meets some
expectations (4)
Meets some
expectations (4)
Meets some
expectations
(10)
Meets some
expectations (2)
Meets some
expectations (4)
Meets some
expectations (4)
Meets some
expectations
(10)
Meets some
expectations (2)
Meets all
expectations
(20)
Meets all
expectations (4)
Meets all
expectations (8)
Meets all
expectations (8)
Meets all
expectations
(20)
Meets all
expectations (4)
Meets all
expectations (8)
Meets all
expectations (8)
Meets all
expectations
(20)
Meets all
expectations (4)
Points
20
4
8
8
20
4
8
8
20
4
Specifications
Justification of
Specifications
Format, layout,
and Language
Does not meet
expectations (0)
Does not meet
expectations (0)
Does not meet
expectations (0)
Meets some
expectations (4)
Meets some
expectations (4)
Meets some
expectations
(2.5)
Meets all
expectations (8)
Meets all
expectations (8)
Meets all
expectations (5)
8
8
10
Late penalty: 10% deduction for each day up to 3 days. After 3 days the grade will be 0.
Article
pubs.acs.org/OPRD
A Simple and Commercially Viable Process for Improved Yields of
Metopimazine, a Dopamine D2‑Receptor Antagonist
Venumanikanta Karicherla, Kumar Phani, Mohan Reddy Bodireddy, Kumar Babu Prashanth,
Madhusudana Rao Gajula,* and Kumar Pramod*
Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, Fourth Phase,
Bommasandra-Jigani Link Road, Bommasandra, Bangalore, Karnataka 560 105, India
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See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information
*
ABSTRACT: An efficient, practical, and commercially viable manufacturing process was developed with ≥99.7% purity and 31%
overall yield (including four chemical reactions and one recrystallization) for an active pharmaceutical ingredient, called
Metopimazine (1), an antiemetic drug used to prevent emesis during chemotherapy. The development of two in situ, one-pot
methods in the present synthetic route helped to improve the overall yield of 1 (31%) compared with earlier reports (60 °C.
To study the effect of NaOH on the course of the reaction,
the same reaction was carried out in the presence of NaOH, but
the formation of compound 5 was low (68%) even after 6 h
with increased formation of impurities (10% of 5a and 8% of
5b) compared with the reaction in KOH.
When we studied the effect of temperature on the course of
reaction (e.g., 20−30 °C, 30−40 °C, and 40−50 °C in acetone)
20%, 35%, and 66% of compound 5 was formed, respectively
(entries 4−6, Table 7). The study disclosed that the optimum
temperature for maximum formation (84%) of compound 5
was 50−60 °C (entry 3, Table 7 and Figure S40, Supporting
Information)
Then, the effect of load of powdered KOH on the course of
the reaction was studied in acetone (e.g., 1.0, 2.0, 3.0, and 4.0
equiv of powdered KOH), 4%, 20%, 84%, and 69% of
compound 5 was formed, respectively. In 1.0 equiv of KOH,
low formation of compound 5 was observed. The deprotection
large amount of water is required to isolate compound 4. To
overcome these issues, we replaced acetic acid with lactic acid
and also DMF with acetonitrile. Accordingly, the same reaction
was carried out in acetonitrile using Zn/lactic acid as selective
reducing agent, and the conversion increased up to 83% (4)
(entry 2, Table 6). In addition, the lactic acid is an
environmentally benign, nonvolatile, and biodegradable green
reagent.26,27 The solvent, acetonitrile, was recovered after the
completion of the reaction, and it is one of the added
advantages over DMF.
With the help of the modified process, the inevitable
compound 4a that was formed in oxidation process was
successfully converted into the desired compound 4 using a
reduction process. This modification provided improved yield
(85%) of compound 4 compared with previously reported
chemoselective oxidation methods.17−19 The study disclosed
that the conversion of compound 4a to compound 4 was good
in Zn/lactic acid/acetonitrile system (entry 2, Table 6, and
Figure S16, Supporting Information).
New Process Conditions for 10-(3-Chloropropyl)-2(methylsulfonyl)-10H-phenothiazine (5) Derivative. The
conversion of 1-[2-(methylsulfonyl)-5-oxido-10H-phenothiazin-10-yl]ethanone (4) to 10-(3-chloropropyl)-2-(methylsulfonyl)-10H-phenothiazine (5) in the presence of base using 1bromo-3-chloropropane was achieved through deprotection
followed by in situ N-alkylation as shown in Scheme 6.
The reaction of compound 4 in the presence of KOH using
1-bromo-3-chloropropane in dichloromethane at reflux temperature provided 40% of compound 5 through deprotection
followed by in situ N-alkylation in one-pot (entry 1, Table 7)
along with 15% of impurity 5a and 3% of impurity 5b. To
improve the conversion further, the same reaction was carried
out at 50−60 °C using ethyl acetate, acetone, acetonitrile, THF,
DMSO, and DMF and 35%, 84%, 42%, 35%, 61%, and 64% of
725
DOI: 10.1021/acs.oprd.7b00052
Org. Process Res. Dev. 2017, 21, 720−731
Organic Process Research & Development
Article
K2CO3 at reflux temperature, and the reaction was unsuccessful
(entry 1, Table 9). The same reaction was carried out in ethyl
acetate, acetone, and methanol at reflux temperature, but the
reaction was unsuccessful (entries 2−4). It is due to inadequate
temperature. If the same reaction was conducted in toluene at
reflux temperature, then 50% of compound 1 and 1% of
impurity 1a and 2% of impurity 1b were formed (entry 5).
The same reaction was carried out in alcoholic solvents and
also in acetonitrile at reflux temperature, and the formation of
compound 1 was low (43−47%) along with 1−2% of impurity
1a and 1−3% of impurity 1b (entries 6−9, Table 9).
Interestingly, in DMAc, the conversion was very low (30%)
with 1% of impurity 1a and 2% of impurity 1b (entry 10).
However, in the case of DMSO and DMF, 51% and 63% of
compound 1 was formed, respectively (entries 11 and 12) in
the presence of K2CO3 at 90−100 °C. In DMSO and DMF, 2%
of impurity 1a and 1% and 12% impurity 1b was formed,
respectively. It is found that in DMF, the conversion was good
(63%) (entry 12). It was observed that both in toluene (entry
5) and DMF (entry 12), the conversion was good compared to
other single solvents (entries 1−4 and 6−11). This encouraged
us to study the effect of mixture of toluene and DMF. For
example, in the mixture of toluene−DMF in 4:6, 5:5, 6:4, 7:3,
8:2, and 9:1 ratio, 63%, 68%, 70%, 72%, 81%, and 73% of
compound 1 was formed, respectively (entries 13−17 and 24,
Table 9). With a decrease in the DMF ratio (e.g., a decrease
from 6 to 2), the formation of impurity 1a decreased from 5%
to 1.5%, and impurity 1b also decreased from 11% to 8%
(entries 13−17). Interestingly, a further decrease of the DMF
ratio leads to an increase of impurities (3% of 1a and 10% of
1b; see entry 24).
The study revealed that the formation of compound 1 (81%)
was good, and the impurities profile (1.5% of 1a and 8% of 1b)
is also tolerable in 8:2 ratio of toluene−DMF mixture (entry
17, Table 9 and Figure S59, Supporting Information).
Then, the effect of base on the course of reaction was studied
(e.g., Na2CO3, Et3N, and piperidine in toluene/DMF (8:2
ratio)), and the conversion was 67%, 31%, and 37%,
respectively (entries 18−20, Table 9). The formation of
impurities in the presence of K2CO3 was low (1.5% of 1a
and 8% of 1b) compared with Na2CO3 and Et3N. In presence
of piperidine, the conversion was not acceptable (37%), but the
formation of impurities was considerably lower (1% of 1a and
2% 1b). The investigation revealed that K2CO3 is a suitable
base for the maximum conversion (81%) with acceptable
impurities profile (entry 17, Table 9 and Figure S59,
Supporting Information).
Then, the effect of temperature on the course of reaction was
studied in toluene/DMF (8:2 ratio). Accordingly, a reaction of
of compound 4 was completed, but N-alkylation was not
proceeding because of insufficient KOH. In the case of 2.0
equiv of KOH, the same situation was observed, but the
formation of 5 was increased (20%) slightly. When the same
reaction was allowed to occur in the presence of 4.0 equiv of
KOH, the formation of 5 decreased (69%) as the formation of
impurities increased (20% of 5a and 4% of 5b). The study
revealed that 3.0 equiv of powdered KOH in acetone provided
the maximum formation of 5 (84%) along with 9% of impurity
5a and 1.5% of impurity 5b (Figure S40, Supporting
Information).
The formation of a potential impurity (5a) was at a high level
(9%) (entry 3, Table 7), which severely affects the required
quality of the obtained API. Hence, its removal is mandatory up
to the level of not more than 2.5%. Therefore, we planned to
improve the quality of compound 5 by isolating it in different
solvents (e.g., acetone, methanol, ethanol, acetonitrile, and
ethyl acetate), and the obtained results were presented in Table
8 (entries 1−5). The study disclosed that methanol was the
Table 8. Selection of Suitable Solvent for Isolation of
Compound 5a
purity (% by HPLC)
entry
solvent
yieldb (%)
product
5
5a
5b
1
2
3
4
5
acetone
methanol
ethanol
acetonitrile
ethyl acetate
65
60
64
66
68
5
5
5
5
5
89
96
91
90
89
05
02
04
06
07
01
1.2
01
01
01
a
Reaction conditions: crude compound 5 (10 g, 0.031 mol) in solvent
(100 mL) at reflux temperature for 30 min, cool to 20−30 °C, stir for
1 h and filter the solid. bIsolated yield.
best option to isolate the desired compound 5 and also to
remove the potential impurity 5a up to the process capability
level (