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  • Sunday 11 August 2019

    [How To] Perform & Evaluate DSC(Differential Scanning Calorimetry) study

    Hiii all....!!
    Good day everyone, hope everything is going good.

    After a gap, back with a most waited post i.e., DSC study generation & evaluation.

    I think everyone is well aware of this and what importance it holds during detailing of safety aspects prior product manufacturing.

    DSC is abbreviated Differential Scanning Calorimetry.

    Most of the small scale pharmaceutical companies wont spare time for generating and evaluating these and it will results in large scale disasters. Whenever a manufacturing process is developed and taken into site for execution trials, the process shall undergo DSC analysis by default.

    It will be the duty of an engineer who handles the manufacturing process at site level

    Before that i'll deliver some basic thing which should be known.

    What is DSC used for ?

    Considering safety aspect, DSC is used to understand the material thermal behavior at various temperatures and to study the decomposition of material. Also Isothermal DSC measurements are used for following applications:

    • Crystallization process which includes polymorphs,
    • Sorption, Vaporisation and drying,
    • Auto-oxidations, polymerization etc.

    What is thermal decomposition ?
    Thermal decomposition is breaking of bonds which is attributed by heat intake. It is something like a chemical change(which cannot be reversed).

    What is the principle of DSC ?

    DSC is a thermo analytical technique. It is used to measure heat variation / enthalphy variation which occur due to the chemical changes in a substances as a function of time and temperature.

    What can be evaluated through DSC study ?

    DSC helps us to understand the material characteristics with respect to temperature and time. It helps in understanding the decomposition temperature, Heat liberation during decomposition, available exotherms in the process or in the operating range, time impact on decomposition temperature.

    What are the alternatives for DSC ?

    There are other alternatives available for DSC. They are TMA (Thermo-Mechanical Analysis), DMA (Dynamic Mechanical Analysis), ARC (Accelerated Rate Calorimetry).

    Is the DSC method accurate ? 

    DSC is just a screening method and not much accurate. But can be trusted if the process is not much critical.

    What can be preferred against DSC in critical case ?

    As per me, if the process is critical, its better move ahead with ARC(Accelerated Rate Calorimetry). 

    What makes ARC more accurate than DSC ?

    DSC shall be performed with a differential temperature of 5 °C/min and the temperature is a variable, whereas ARC requires more time, the differential temperature would be 0.001°C/min.

    What is the parameter used in DSC ?

    DSC measures the change in enthalphy, i.e., dH/dt and the graph is plotted between 
    dH/dt VS temperature.

    Also Read:
    Checking batch size feasibility for scale-up 

    Guidelines for process development

    What are the cases which requires ARC ?

    Usually after performing DSC, the tentative decomposition temperature would be revealed and if the decomposition temperature is nearby the operating temperature, it would be advisable to understand the exact temperature of decomposition. Based on the evaluation, appropriate mitigation plan can be designed.

    What is the type of system used for DSC study ?

    DSC study can be done two types of systems i.e., Heat Flux DSC & Power Compensated DSC. Usually we'll prefer Heat flux DSC for pharmaceutical intermediates & API's.

    Heat flux DSC heats the two pans (Sample pan & Reference pan) on a single heater with single heat flux and the temperature difference shall be converted to power difference. Power difference(watts) can be represents the variation in heat flow in both cases.

    In Power compensated DSC, reference pan and sample pan shall be heated separately and the pan temperatures shall be monitored using thermo-couples. The connected thermocouples measures the differential heat flow.

    What are the possible thermal events during DSC study ?

    A (S1)                     ------- >   A (S2)  - Phase transition,
    A (S1)                     ------- >   A (L)  - Melting,
    A (S1)                     ------- >   A (G) - Sublimation,
    A (S1)                     ------- >   B (S) + Gasses (or) Gasses - Decomposition

    Here, S1 refers to Solid-1, S2 refers to Solid-2, L refers to Liquid, G refers to gas.

    And finally, what is TMR ?

    TMR refers to time to maximum rate. Simply it is the time taken by reaction mass to attain/reach maximum heat liberation rate.

    Delivered the basic stuff above. Let's jump into the topic.

    How To Perform DSC analysis:

    DSC is a measure thermal enthalphy, for measuring the enthalphy we need a reference.

    Two pans will be considered for the study, out of which one will be a reference pan(empty pan P - 1 ), second one will be filled with material (P-2) which need to be studied.

    Also Read:
    Evaluate filtration feasibility in ANFD 
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    A sample of ~5 to 10 grams shall be filled in the pan and care shall be taken to avoid any gaps in the pan i.e., material shall cover the heat transfer surface of pan.

    These two pans shall be placed on the heater and shall be heated slowly. The whole system shall be connected to the computer and the system shall be operated.

    The process of heating pans will come under dynamic run with an pre-defined temperature gradient i.e., like 2℃/min or 5℃/min. It is based on our convenience. Usually the dynamic run shall be  started from RT temperature. (During this dynamic run, system will stabilize initially).

    As the Pan - 2 contains sample, the intake heat will be somewhat higher than that of the reference pan - 1.

    The dH/dt will be plotted against the temperature and the graph will look like this:
    As pert the above graph, there is an exotherm (the peak above reference line) observed at 137.16℃ with a liberation of 36.36 J/g and an endotherm (peak below reference line) is observed at 232.32with an intake of 40.13 J/g.

    Through the dynamic run, we'll be able to identify the product decomposition temperature and the available exotherms and endotherms in the path.

    Also Read:
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    The energy liberation / requirement during the particular duration is given by 

    q = qo x e^(-Ea/RT).

    q    - Heat liberated / consumed at the temperature T,
    qo  - Threshold energy of the material (Constant),
    Ea  - Activation energy,
    R    - Universal gas constant,
    T    - Temperature.

    In order to calculate the TMR (Time to maximum rate), we need to calculate the threshold energy and activation energy of the material. For that we have to perform a minimum of two iso-thermal runs.

    1st iso-thermal run shall be performed at the onset of decomposition i.e., 137.16 °C with an energy liberation of 36.36 J/g. So the first equation will be like

    36.36 x 5 = qo x e^(-Ea/(8.314 x (137.16 + 273.15)))

    181.8 = qo x e^(-Ea/3411.32) ------ ( 1 )

    2nd iso-thermal run shall be performed at the temperature approximately 15-20°C less than that of the onset temperature. Lets say, the temperature is 120°C. So the second equation will be like

    27 x 5 = qo x e^(-Ea/(8.314 x (120 + 273.15)))  [** 27 j/g is the considered value, not derived one]

    135 = qo x e^(-Ea/3268.65) -------- ( 2 )

    These two equations need to be resolved to get qo, Ea values.

    Eq. ( 2 ) - Eq. (1) => log(135/181.8) = (-Ea/R) x [(1/120) - (1/137.16)]

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    Upon resolving,

    Ea = 10102.36 J/mole
    qo = 3481.77 Joules = 3481.77/5 J/g = 696.35 J/g [** 5 is the sample Qty.]
    Now, TMR can be calculated from the below formula,

    TMR = (Cp x R x T^2)/(q x Eo), in hours

    Lets calculate the time to maximum rate at 140 °C,

    q = 696.35 x e^(-10102.36/(8.314 x (140+273.15))) = 37.105 J/g.

    TMR = (2 x 8.314 x (273.15+140)^2) / (37.105 x 10102.36) = 7.57 hours.
    [Cp = 2 J/g. K considered].

    i.e., if we maintain the reaction mass at 140°C for a span of 7.57 hours, maximum heat liberation will be observed.

    That's it....!!!

    Hope it is clear for all.........!!!

    If any queries, feel free to comment.......!!!

    Comments are most appreciated.........!!!

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    About The Author

    Hi! I am Ajay Kumar Kalva, Currently serving as the CEO of this site, a tech geek by passion, and a chemical process engineer by profession, i'm interested in writing articles regarding technology, hacking and pharma technology.
    Follow Me on Twitter AjaySpectator & Computer Innovations


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    10. Highly Informative post regarding DSC analysis and evaluation
      I think sample size is in mg scale (2 to 10mg) which is one of the reason we prefer for ARC analysis

      1. But ARC requires higher durations due to lower ramp rise,
        As per me its better and effective if we perform DSC initially to understand the behaviour and then followed by ARC(if required).

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      1. Dear Vinod,

        Basically I'm a process engineer working in a pharma industry and that's my first priority and if i find sometime i'll land here to share. Due to my regular job role i'll be rotating in shifts, so it will be difficult to spend time.

    13. For what type of raw material we can go for DSC


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