Peptide therapeutics are one of the fastest-growing areas in the pharmaceutical pipeline. Market projections vary among reporting agencies, yet peptide therapeutics continue to demonstrate strong commercial growth (Lau & Dunn, 2018; Muttenthaler et al., 2021). Peptides exist in a chemical realm that small molecules struggle to penetrate able to interfere with protein–protein interactions, imitate natural signaling molecules, and attain selective profiles that minimize off-target toxicity (Muttenthaler et al., 2021). The clinical efficacy of tirzepatide and semaglutide for type 2 diabetes and obesity has demonstrated that peptide APIs can achieve blockbuster commercial levels, significantly boosting global demand for large-scale peptide manufacturing (Muttenthaler et al., 2021; Martin et al., 2020).
At the centre of this manufacturing dilemma lies a question that is both technical and financial: which synthesis platform most effectively supports a specific peptide project? Although the two most popular approaches—SPPS and LPPS—have both advanced significantly over the past 30 years, their benefits still depend on the situation. SPPS, initially introduced by Merrifield (1963) and later enhanced via Fmoc chemistry, has become the leading method for research and initial production due to its suitability for automation and capacity to enable rapid peptide construction (Behrendt et al., 2016). LPPS remains an important manufacturing method for short peptides and peptide intermediates, particularly in large-scale production where efficient isolation, purification through crystallization, and reduced reliance on solid supports can improve economics (Isidro-Llobet et al., 2019; Martin et
al., 2020).
Peptide production decisions are increasingly being influenced by sustainability considerations, particularly due to concerns about solvent consumption and process mass intensity (Isidro-Llobet et al., 2019). Green chemistry initiatives are urging manufacturers to reevaluate their choice of solvents in SPPS (Wegner et al., 2021). Convergent synthetic techniques that combine SPPS-derived segments with solution-phase coupling are increasingly being used for long and structurally complex peptides (Albericio et al., 1997; de la Torre & Albericio, 2022). Continuous-flow peptide synthesis has emerged as a viable alternative for conventional batch processing, providing reduced reaction times, better process control, and increased throughput for specific peptide manufacturing uses (Coin et al., 2007; Mijalis et al., 2017). In light of this, a comprehensive, evidence-based evaluation of the two primary synthesis platforms—examined from the perspective of cost-effectiveness— addresses a distinct requirement for both purchasing decision-makers and industrial practitioners. This review thoroughly assesses the comparative benefits and limitations of SPPS and LPPS in contemporary peptide production, highlighting aspects that affect cost-effectiveness, scalability, sustainability, and process selection.
In SPPS, the desired sequence’s C-terminal amino acid is first attached to a non-soluble polymer resin, and the chain is then gradually extended towards the N-terminus. Every elongation cycle includes the removal of the temporary alpha-amine protecting group, followed by a washing phase, the coupling of the subsequent activated amino acid, and a final washing step to eliminate excess reagents (Amblard et al., 2006). Fmoc chemistry has emerged as the primary protection strategy in modern SPPS due to its compatibility with various side-chain protecting groups and its elimination of hydrogen fluoride needed for final cleavage in Boc-based methods (Behrendt et al., 2016).
The primary advantage of SPPS is how simple coupling operations are. Reactions are accelerated by excess reagents, and unreacted materials are simply rinsed out rather than chemically separated. This design allows automation on commercial synthesizers capable to execute multiple parallel sequences at the same time (Mäde et al., 2014). Contemporary microwave-assisted and automated peptide synthesizers have significantly reduced the length of synthesis cycles and increased productivity for typical peptide production.
After synthesis, purification has the biggest financial impact on SPPS. Deletion sequences, racemized residues, and partially deprotected side chains are common components of crude SPPS products that require purification using preparative reverse-phase high-performance liquid chromatography (RP- HPLC). Purification often constitutes a significant factor in the total cost of manufacturing (Behrendt et al., 2016; Martin et al., 2020). At the industrial level, the use of solvents—DMF, acetonitrile, and dichloromethane are the primary solvents—raising costs and environmental concerns (Isidro-Llobet et al., 2019)
LPPS carries out every coupling and deprotection step in a homogeneous solution. Before proceeding to the next stage, the growing peptide intermediate is separated by precipitation, crystallization, or chromatographic methods after each reaction. The need for intermediate isolation raises the intricacy of the process and may decrease operational efficiency as the length of the peptide increases (Verlander, 2007). However, LPPS is still appealing for short peptides and peptide intermediates, particularly when crystallization purification may be used to obtain high-purity intermediates without requiring extensive chromatography steps.
When large-scale solution-phase processing and economical crystallization-based purification can be used, liquid-phase peptide synthesis remains an essential commercial technique for generating short peptides and peptide intermediates (Verlander, 2007; Martin et al. 2020). At extensive manufacturing levels, LPPS prevents resin swelling and solid-phase mass-transfer limitations that can hinder process scale-up in SPPS (Isidro-Llobet et al., 2019; Martin et al., 2020). Through efficient solution-phase processing and reduced reliance on chromatographic purification, LPPS can offer economic advantages for the large-scale production of short peptide APIs.
The conventional distinction of solid-phase peptide synthesis (SPPS) and liquid-phase peptide
synthesis (LPPS) is progressively being enhanced by new technologies focused on improving
efficiency, sustainability, and scalability. Recent advancements in peptide manufacturing involves
automated chemputation systems, continuous-flow peptide synthesis, and the use of green chemistry
methods to reduce waste output and enhance process efficiency. These advancements are intended to address significant shortcomings of conventional peptide synthesis, including high solvent
consumption, lengthy synthesis periods, and challenges in producing structurally complex peptides (Cai et al., 2025).
Among these advancements, hybrid synthesis methods have attracted considerable interest as effective approaches for producing longer and more intricate peptide therapeutics. Hybrid methods often merge the rapid fragment assembly functions of SPPS with solution-phase fragment condensation techniques, enabling producers to lessen the overall effects of incomplete coupling reactions linked to extensive linear syntheses. Utilizing the complementary advantages of both platforms, hybrid approaches can enhance synthetic efficiency, facilitate scale-up, and provide access to peptide structures that might be challenging to acquire through either SPPS or LPPS alone (Cai et al., 2025).
An important industrial use of hybrid peptide synthesis is the kilogram-scale GMP production of tirzepatide, with SPPS utilized to produce peptide fragments that were later combined through LPPS
processes. To increase yield, purity, and process reliability, the approach combined continuous
production technology, real-time analytical monitoring, and intermediate purification by
nanofiltration. This hybrid SPPS/LPPS approach was designed to tackle the manufacturing difficulties
linked to complex therapeutic peptides, showcasing how the combined benefits of solid-phase and
solution-phase synthesis can be united to facilitate scalable commercial production (Frederick et al.,
2021).
The concept of hybridization has expanded beyond manufacturing to include peptide therapeutic
research. Peptide–drug conjugates and peptide–small molecule hybrids merge the targeting precision of peptides with the pharmacological benefits of small molecules, improving metabolic stability, cellular absorption, and therapeutic effectiveness. These adaptable systems are increasingly being investigated in infectious diseases, oncology, and metabolic disorders, highlighting the growing
importance of hybrid technologies in peptide synthesis and advanced drug development (Dean et al.,
2024; Wu et al., 2021).
Collectively, these advancements demonstrate the shift in peptide synthesis from the conventional
SPPS-versus-LPPS model to combined manufacturing approaches that emphasize efficiency, sustainability, and molecular intricacy. With the growing complexity and market demand for therapeutic peptides, hybrid and continuous manufacturing technologies are anticipated to become
increasingly crucial in future peptide production
Cost for raw materials in SPPS include resin, Fmoc-protected amino acids featuring orthogonal side-
chain protection, coupling agents (usually HATU and HBTU), and bases (piperidine or morpholineused for deprotection). Coupling reagents account for a significant portion of raw material costs in
SPPS, particularly for complex sequences requiring several coupling cycles. The capacity for resin loading and the selection of resin, play a crucial role in the use of reagents and the overall efficiency
of the process in SPPS (Behrendt et al., 2016).
Because protecting group chemistry is simplified in LPPSusing a single protecting group method
rather than the numerous orthogonal protections required for SPPS the cost of raw materials is
typically lower per mole of peptide bond formed. Compared to SPPS, LPPS can achieve superior atom
economy and may require fewer protected intermediates for short peptide sequences. However, this
advantage decreases rapidly as chain lengthens and additional isolation steps proliferate (Verlander,
2007).
Automation has greatly enhanced the efficiency of SPPS by minimizing manual handling and allowing
for unattended execution of repetitive coupling, deprotection, and washing processes. Contemporary
automated synthesizers are capable of generating various peptide sequences with minimal operator
involvement, rendering SPPS especially appealing for research and clinical manufacturing (Mäde et
al., 2014).
In contrast, as peptide length increases, LPPS usually requires the isolation and purification of
intermediates following each synthetic step, increasing process complexity and labor requirements.
While LPPS continues to be beneficial for some short peptides and large-scale industrial uses, the
overall effort of intermediate processing frequently restricts its feasibility for longer sequences
(Verlander, 2007; Amblard et al., 2006).
It is widely accepted that purification has a significant role in the overall cost of producing peptides.
Preparative RP-HPLC setups necessitate considerable financial investment, utilize large quantities of
acetonitrile and water, and create throughput limitations that scale non-linearly with the batch size. It
is frequently considered as one of the most expensive and resource-intensive procedures in the
synthesis of peptides (Henninot et al., 2018).
LPPS, suitable for crystallization, bypasses this HPLC challenge. A well-designed crystallization
process can reduce the need for chromatographic purification and yield extremely pure peptide
intermediates. However, crystallization parameters are sequence-specific and must be determined
empirically; this development expenditure is only justified for products with large volumes and extended lifespans (Verlander, 2007)
The economic benefits of SPPS and LPPS differ depending on the scale of production and the
complexity of the peptides. Because of its automation, versatility, and speed at producing different
peptide sequences, SPPS remains the top platform for peptide research, discovery, and large-scale
production. Conversely, LPPS may provide benefits for specific short peptides produced in large
quantities, especially when crystallization-based purification is utilized to lower downstream
processing expenses (Verlander, 2007; Martin et al., 2020).
In order to improve scalability, product quality, and overall process efficiency, more manufacturers
are investigating hybrid synthetic approaches and cutting-edge process technologies that combine the strengths of solid-phase and liquid-phase procedures (Hartrampf et al., 2020)
Table 1 summarizes the main factors that distinguish SPPS and LPPS in technological, economic, and regulatory domains.